Logo: to the web site of Uppsala University

uu.sePublications from Uppsala University
Change search
Refine search result
1234 1 - 50 of 172
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia..
    Marklund, Niklas
    Department of Clinical Sciences Lund, Neurosurgery, Skåne University Hospital Lund University, Lund, Sweden .
    Differential DNA methylation of the genes for amyloid precursor protein, tau and neurofilaments in human traumatic brain injury2021In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 38, no 12, p. 1679-1688Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) is an established risk factor for neurodegenerative disorders and dementias. Epigenetic modifications, such as DNA methylation, may alter the expression of genes without altering the DNA sequence in response to environmental factors. We hypothesized that DNA methylation changes may occur in the injured human brain and be implicated in the neurodegenerative aftermath of TBI. The DNA methylation status of genes related to neurodegeneration, e.g. amyloid beta precursor protein (APP), microtubule associated protein tau (MAPT), neurofilament heavy (NEFH), neurofilament medium (NEFM) and neurofilament light (NEFL), was analyzed in fresh, surgically resected human brain tissue from 17 severe TBI patients and compared with brain biopsy samples from 19 patients with idiopathic normal pressure hydrocephalus (iNPH). We also performed an epigenome-wide association study (EWAS) comparing TBI patients to iNPH controls. Thirty-eight CpG sites in the APP, MAPT, NEFH and NEFL genes were differentially methylated by TBI. Among the top 20 differentially methylated CpG sites, 11 were in the APP gene. In addition, the EWAS evaluating 828 888 CpG sites revealed 308 differentially methylated CpG sites in genes related to cellular/anatomical structure development, cell differentiation and anatomical morphogenesis. These preliminary findings provide the first evidence of an altered DNA methylome in the injured human brain and may have implications for the neurodegenerative disorders associated at long-term with TBI. 

  • 2.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rollman Waara, Erik
    BioArctic Neurosci AB, Stockholm, Sweden.
    Möller, Christer
    BioArctic Neurosci AB, Stockholm, Sweden.
    Söderberg, Linda
    BioArctic Neurosci AB, Stockholm, Sweden.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury2018In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 28, no 4, p. 451-462Article in journal (Refereed)
    Abstract [en]

    Deposition of amyloid-β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life-threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n = 5), to post-mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N-terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4-negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI.

  • 3.
    Almandoz-Gil, Leire
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindström, Veronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sigvardson, Jessica
    BioArctic, Stockholm, Sweden.
    Kahle, Philipp J.
    Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat, Lab Funct Neurogenet, Tubingen, Germany.;German Ctr Neurodegenerat Dis, Tubingen, Germany..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Mapping of Surface-Exposed Epitopes of In Vitro and In Vivo Aggregated Species of Alpha-Synuclein2017In: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 37, no 7, p. 1217-1226Article in journal (Refereed)
    Abstract [en]

    Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal deposits observed in Parkinson's disease and dementia with Lewy bodies. The objective of the study was to identify surface-exposed epitopes of alpha-synuclein in vitro and in vivo formed aggregates. Polyclonal immunoglobulin Y antibodies were raised against short linear peptides of the alpha-synuclein molecule. An epitope in the N-terminal region (1-10) and all C-terminal epitopes (90-140) were found to be exposed in an indirect enzyme-linked immunosorbent assay (ELISA) using recombinant monomeric, oligomeric, and fibrillar alpha-synuclein. In a phospholipid ELISA, the N-terminus and mid-region of alpha-synuclein (i.e., 1-90) were associated with phosphatidylserine and thus occluded from antibody binding. The antibodies that reacted most strongly with epitopes in the in vitro aggregates (i.e., 1-10 and epitopes between positions 90-140) also labeled alpha-synuclein inclusions in brains from transgenic (Thy-1)-h[A30P] alpha-synuclein mice and Lewy bodies and Lewy neurites in brains of patients with alpha-synucleinopathies. However, differences in reactivity were observed with the C-terminal antibodies when brain tissue from human and transgenic mice was compared. Taken together, the study shows that although similar epitopes are exposed in both in vitro and in vivo formed alpha-synuclein inclusions, structural heterogeneity can be observed between different molecular species.

    Download full text (pdf)
    fulltext
  • 4.
    Almandoz-Gil, Leire
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Persson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindström, Veronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    In situ proximity ligation assay reveals co-localization of alpha-synuclein and SNARE proteins in murine primary neurons2018In: Frontiers in Neurology, E-ISSN 1664-2295, Vol. 9, article id 180Article in journal (Refereed)
    Abstract [en]

    The aggregation of alpha-synuclein (alpha Syn) is the pathological hallmark of Parkinson's disease, dementia with Lewy bodies and related neurological disorders. However, the physiological function of the protein and how this function relates to its pathological effects remain poorly understood. One of the proposed roles of aSyn is to promote the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to VAMP-2. The objective of this study was to visualize the co-localization between aSyn and the SNARE proteins (VAMP-2, SNAP-25, and syntaxin-1) for the first time using in situ proximity ligation assay (PLA). Cortical primary neurons were cultured from either non-transgenic or transgenic mice expressing human aSyn with the A30P mutation under the Thy-1 promoter. With an antibody recognizing both mouse and human aSyn, a PLA signal indicating close proximity between aSyn and the three SNARE proteins was observed both in the soma and throughout the processes. No differences in the extent of PLA signals were seen between non-transgenic and transgenic neurons. With an antibody specific against human aSyn, the PLA signal was mostly located to the soma and was only present in a few cells. Taken together, in situ PLA is a method that can be used to investigate the co-localization of aSyn and the SNARE proteins in primary neuronal cultures

    Download full text (pdf)
    fulltext
  • 5.
    Almandoz-Gil, Leire
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Welander, Hedvig
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ihse, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Khoonsari, Payam Emami
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Lendel, Christofer
    KTH, Royal Institute of Technology, Sweden.
    Sigvardson, Jessica
    BioArctic AB, Sweden.
    Karlsson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways2017In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 110, p. 421-431Article in journal (Refereed)
    Abstract [en]

    Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal inclusions found in brains with Parkinson's disease and dementia with Lewy bodies. A body of evidence implicates oxidative stress in the pathogenesis of these diseases. For example, a large excess (30:1, aldehyde:protein) of the lipid peroxidation end products 4-oxo-2-nonenal (ONE) or 4-hydroxy-2-nonenal (HNE) can induce alpha-synuclein oligomer formation. The objective of the study was to investigate the effect of these reactive aldehydes on alpha-synuclein at a lower molar excess (3:1) at both physiological (7.4) and acidic (5.4) pH. As observed by size-exclusion chromatography, ONE rapidly induced the formation of alpha-synuclein oligomers at both pH values, but the effect was less pronounced under the acidic condition. In contrast, only a small proportion of alpha-synuclein oligomers were formed with low excess HNE-treatment at physiological pH and no oligomers at all under the acidic condition. With prolonged incubation times (up to 96 h), more alpha-synuclein was oligomerized at physiological pH for both ONE and HNE. As determined by Western blot, ONE-oligomers were more SDS-stable and to a higher-degree cross-linked as compared to the HNE-induced oligomers. However, as shown by their greater sensitivity to proteinase K treatment, ONE-oligomers, exhibited a less compact structure than HNE-oligomers. As indicated by mass spectrometry, ONE modified most Lys residues, whereas HNE primarily modified the His50 residue and fewer Lys residues, albeit to a higher degree than ONE. Taken together, our data show that the aldehydes ONE and HNE can modify alpha-synuclein and induce oligomerization, even at low molar excess, but to a higher degree at physiological pH and seemingly through different pathways.

    Download full text (pdf)
    fulltext
    Download (pdf)
    errata
  • 6.
    Aniszewska, Agata
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada. Univ Toronto, Dept Med, Toronto, ON, Canada. Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada..
    Ekmark-Lewén, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Modeling Parkinson's disease-related symptoms in alpha-synuclein overexpressing mice2022In: Brain and Behavior, ISSN 2162-3279, E-ISSN 2162-3279, Vol. 12, no 7, article id e2628Article, review/survey (Refereed)
    Abstract [en]

    Background: Intracellular deposition of alpha-synuclein (alpha-syn) as Lewy bodies and Lewy neurites is a central event in the pathogenesis of Parkinson's disease (PD) and other alpha-synucleinopathies. Transgenic mouse models overexpressing human alpha-syn, are useful research tools in preclinical studies of pathogenetic mechanisms. Such mice develop alpha-syn inclusions as well as neurodegeneration with a topographical distribution that varies depending on the choice of promoter and which form of alpha-syn that is overexpressed. Moreover, they display motor symptoms and cognitive disturbances that to some extent resemble the human conditions.

    Purpose: One of the main motives for assessing behavior in these mouse models is to evaluate the potential of new treatment strategies, including their impact on motor and cognitive symptoms. However, due to a high within-group variability with respect to such features, the behavioral studies need to be applied with caution. In this review, we discuss how to make appropriate choices in the experimental design and which tests that are most suitable for the evaluation of PD-related symptoms in such studies.

    Methods: We have evaluated published results on two selected transgenic mouse models overexpressing wild type (L61) and mutated (A30P) alpha-syn in the context of their validity and utility for different types of behavioral studies.

    Conclusions: By applying appropriate behavioral tests, alpha-syn transgenic mouse models provide an appropriate experimental platform for studies of symptoms related to PD and other alpha-synucleinopathies.

    Download full text (pdf)
    fulltext
  • 7. Antonios, Gregory
    et al.
    Saiepour, Nasrin
    Bouter, Yvonne
    Richard, Bernhard C
    Paetau, Anders
    Verkkoniemi-Ahola, Auli
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kovacs, Gabor G
    Pillot, Thierry
    Wirths, Oliver
    Bayer, Thomas A
    N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody2013In: Acta neuropathologica communications, ISSN 2051-5960, Vol. 1, no 1, p. 56-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The amyloid hypothesis in Alzheimer disease (AD) considers amyloid β peptide (Aβ) deposition causative in triggering down-stream events like neurofibrillary tangles, cell loss, vascular damage and memory decline. In the past years N-truncated Aβ peptides especially N-truncated pyroglutamate AβpE3-42 have been extensively studied. Together with full-length Aβ1-42 and Aβ1-40, N-truncated AβpE3-42 and Aβ4-42 are major variants in AD brain. Although Aβ4-42 has been known for a much longer time, there is a lack of studies addressing the question whether AβpE3-42 or Aβ4-42 may precede the other in Alzheimer's disease pathology.

    RESULTS: Using different Aβ antibodies specific for the different N-termini of N-truncated Aβ, we discovered that Aβ4-x preceded AβpE3-x intraneuronal accumulation in a transgenic mouse model for AD prior to plaque formation. The novel Aβ4-x immunoreactive antibody NT4X-167 detected high molecular weight aggregates derived from N-truncated Aβ species. While NT4X-167 significantly rescued Aβ4-42 toxicity in vitro no beneficial effect was observed against Aβ1-42 or AβpE3-42 toxicity. Phenylalanine at position four of Aβ was imperative for antibody binding, because its replacement with alanine or proline completely prevented binding. Although amyloid plaques were observed using NT4X-167 in 5XFAD transgenic mice, it barely reacted with plaques in the brain of sporadic AD patients and familial cases with the Arctic, Swedish and the presenilin-1 PS1Δ9 mutation. A consistent staining was observed in blood vessels in all AD cases with cerebral amyloid angiopathy. There was no cross-reactivity with other aggregates typical for other common neurodegenerative diseases showing that NT4X-167 staining is specific for AD.

    CONCLUSIONS: Aβ4-x precedes AβpE3-x in the well accepted 5XFAD AD mouse model underlining the significance of N-truncated species in AD pathology. NT4X-167 therefore is the first antibody reacting with Aβ4-x and represents a novel tool in Alzheimer research.

  • 8.
    Aoyagi, Atsushi
    et al.
    Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA;Daiichi Sankyo Co Ltd, Tokyo 1408710, Japan.
    Condello, Carlo
    Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA;Univ Calif San Francisco, UCSF Weill Inst Neurosci, Dept Neurol, San Francisco, CA 94158 USA.
    Stöhr, Jan
    Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA;Univ Calif San Francisco, UCSF Weill Inst Neurosci, Dept Neurol, San Francisco, CA 94158 USA;AC Immune SA, EPFL Innovat Pk,Bldg B, CH-1015 Lausanne, Switzerland.
    Yue, Weizhou
    Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.
    Rivera, Brianna M.
    Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.
    Lee, Joanne C.
    Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.
    Woerman, Amanda L.
    Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA;Univ Calif San Francisco, UCSF Weill Inst Neurosci, Dept Neurol, San Francisco, CA 94158 USA.
    Halliday, Glenda
    Univ New South Wales, NeuRA, Sydney, NSW 2052, Australia;Univ New South Wales, Sch Med Sci, Sydney, NSW 2052, Australia;Univ Sydney, Brain & Mind Ctr, Sydney, NSW 2052, Australia.
    van Duinen, Sjoerd
    Leiden Univ, Med Ctr, Leiden, Netherlands.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Graff, Caroline
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Solna, Sweden;Karolinska Univ Hosp, Unit Hereditary Dementias, Theme Aging, Solna, Sweden.
    Bird, Thomas D.
    Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA;Univ Washington, Dept Neurol, Seattle, WA 98195 USA.
    Keene, C. Dirk
    Univ Washington, Dept Neuropathol, Sch Med, Seattle, WA 98195 USA.
    Seeley, William W.
    Univ Calif San Francisco, UCSF Weill Inst Neurosci, Dept Neurol, San Francisco, CA 94158 USA;Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA.
    DeGrado, William F.
    Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA;Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA.
    Prusiner, Stanley B.
    Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA;Univ Calif San Francisco, UCSF Weill Inst Neurosci, Dept Neurol, San Francisco, CA 94158 USA;Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA.
    A beta and tau prion-like activities decline with longevity in the Alzheimer's disease human brain2019In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 11, no 490, article id eaat8462Article in journal (Refereed)
    Abstract [en]

    The hallmarks of Alzheimer's disease (AD) are the accumulation of A beta plaques and neurofibrillary tangles composed of hyperphosphorylated tau. We developed sensitive cellular assays using human embryonic kidney-293T cells to quantify intracellular self-propagating conformers of A beta in brain samples from patients with AD or other neurodegenerative diseases. Postmortem brain tissue from patients with AD had measurable amounts of pathological A beta conformers. Individuals over 80 years of age had the lowest amounts of prion-like A beta and phosphorylated tau. Unexpectedly, the longevity-dependent decrease in self-propagating tau conformers occurred in spite of increasing amounts of total insoluble tau. When corrected for the abundance of insoluble tau, the ability of postmortem AD brain homogenates to induce misfolded tau in the cellular assays showed an exponential decrease with longevity, with a half-life of about one decade over the age range of 37 to 99 years. Thus, our findings demonstrate an inverse correlation between longevity in patients with AD and the abundance of pathological tau conformers. Our cellular assays can be applied to patient selection for clinical studies and the development of new drugs and diagnostics for AD.

  • 9.
    Basun, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Bogdanovic, Nenad
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Almkvist, Ove
    Näslund, Jan
    Axelman, Karin
    Bird, Thomas D
    Nochlin, David
    Schellenberg, Gerard D
    Wahlund, Lars-Olof
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Clinical and Neuropathological Features of the Arctic APP Gene Mutation Causing Early-Onset Alzheimer Disease2008In: Archives of Neurology, ISSN 0003-9942, E-ISSN 1538-3687, Vol. 65, no 4, p. 499-505Article in journal (Refereed)
    Abstract [en]

    Background: A majority of mutations within the beta-amyloid region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral hemorrhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra-beta-amyloid mutation to date causing the more typical clinical picture of Alzheimer disease. Objective: To describe features of 1 Swedish and 1 American family with the previously reported Arctic APP mutation. Design, Setting, and Participants: Affected and non-affected carriers of the Arctic APP mutation from the Swedish and American families were investigated clinically. In addition, 1 brain from each family was investigated neuropathologically. Results: The clinical picture, with age at disease onset in the sixth to seventh decade of life and dysfunction in multiple cognitive areas, is indicative of Alzheimer disease and similar to the phenotype for other Alzheimer disease APP mutations. Several affected mutation carriers displayed general brain atrophy and reduced blood flow of the parietal lobe as demonstrated by magnetic resonance imaging and single-photon emission computed tomography. One Swedish case and 1 American case with the Arctic APP mutation came to autopsy, and both showed no signs of hemorrhage but revealed severe congophilic angiopathy, region-specific neurofibrillary tangle pathological findings, and abundant amyloid plaques. Intriguingly, most plaques from both of these cases had a characteristic ringlike character. Conclusions: Overall, our findings corroborate that the Arctic APP mutation causes a clinical and neuropathological picture compatible with Alzheimer disease.

  • 10.
    Behere, Anish
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hårrskog, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Södergren, Moa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ekmark-Lewén, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Alpha synuclein pre-formed fibrils trigger astrocytic activation prior to intra-neuronal deposition in a seeding mouse model of Parkinson’s diseaseManuscript (preprint) (Other academic)
    Abstract [en]

    Aim: To monitor temporal evolution of glial and peripheral events occurring, prior to pSynS129 inclusion formation, after a single intra-cranial injection of pre-formed fibrils (PFFs) in the wild-type (wt) mice.

    Experimental plan: Here we perform intracerebral inoculations with mouse PFFs in wt mice (n=30) to study early pathological and inflammatory events from 1 to 30 days post-injections (dpi) at regular time intervals. The paraffin-fixed brain sections were stained against pSynS129 species with the in house developed  proximity ligation assay. Furthermore, studies using different glial and inflammatory markers revealed more information regarding the early cellular interactions involving formation and propagation pSynS129 species.

    Results: Already after 1 dpi, we observe strong pSynS129 immunoreactivity close the striatal injection site. Intriguingly, this type of staining disappeared with the concurrent formation of peri-nuclear pSynS129 inclusions in motor and piriform cortex, amygdala and periventricular hypothalamus after 14 dpi. Concomitantly, we observed astrocytic activation as early event happening prior to intracellular formation and propagation pSynS129 inclusions in the brain and peripheral organs.

    Significance: Our study elucidates the temporal relationship regarding inflammation and formation of pSynS129 inclusions. Our results indicate that a single PFF injection is enough to induce astrocytic activation and neuro-inflammatory response that occur prior to intra-neuronal accumulation of misfolded α-syn.

  • 11.
    Behere, Anish
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ekmark-Lewén, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    A proximity ligation assay recognizing phosphorylated α-syn reveals previously undetected α-syn pathology in the brains of synucleinopathy patients and mouse model.Manuscript (preprint) (Other academic)
    Abstract [en]

    Aim: To enhance detection sensitivity of phosphorylated α-synuclein (pSynS129) on post mortem synucleinopathy brains using the newly developed PLA and characterize possible ‘strain’-specific differences in the synucleinopathy brains.

    Experimental plan: Four different antibodies detecting different epitopes from N- to C- terminal of α-syn were paired systematically with an antibody detecting pSynS129 to reveal patho-morphological features of α-syn aggregates on post mortem brain tissue. In addition, we tested the application of our novel PLA technique in the A30P-tg mouse model that shows different types of pSynS129 aggregates in different stages of PD.

    Results: The PLA experiments revealed a wide distribution of pSynS129 aggregates in post mortem synucleinopathy-patient brains. We observed unique staining patterns on the brain tissue sections using only certain antibody combinations in a PLA setup, which could not be visualized using regular immunohistochemistry. In A30P-tg mice, the morphological pattern of PLA signal indicated an age-progressive, intracellular shift of pSynS129 aggregation species from periphery towards soma in the prefrontal cortex.

    Significance: Here we demonstrate that employing PLA with certain α-syn antibodies pair combinations can enhance detection sensitivity and specificity of α-syn pathology in the respective synucleinopathies. Additionally, it could be a useful tool to monitor the ‘strain’-specific aggregation and intracellular morphology of α-syn on post mortem brain tissue.

  • 12.
    Behere, Anish
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Novel visualization of phosphorylated tau and alpha-synuclein aggregates in the Alzheimer’s disease and Parkinson’s disease brainManuscript (preprint) (Other academic)
    Abstract [en]

    Several neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), display deposits of phosphorylated tau (pTau) and/or alpha-synuclein (pSyn) in affected parts of the brain. However, the pathological and morphological properties of these protein aggregates remain poorly characterized, due to lack of specificity and sensitivity of in situ detection techniques. The aim of this study was to investigate the patho-morphological properties of phosphorylated tau and α-syn aggregates on AD and PD brain tissues with a novel sensitive in situ proximity ligation assay (PLA) technique. We took advantage of the sensitivity and <40 nm resolution of PLA, along with the selectivity of different antibodies directed against pTau and pSyn epitopes. Most notably, multiplex pTauS202, T205-pTauT231, singleplex pTauT231 and pSynS129 PLA recognized more extensive phosphorylated tau and αSyn pathology, compared to conventional immunohistochemistry (IHC) using the same antibodies on adjacent brain sections. Furthermore, singleplex pTauT231 PLA captured additional pathological aggregates compared to the singleplex pTauS202, T205 PLA in late Braak stage AD brains, where traditional IHC failed to distinguish between pTauS202, T205 and pTauT231 pathology. Similarly, in PD brains, singleplex pSynS129 PLA detected novel pathological structures, such as intercellular thick tunneling nanotubes and pre-Lewy body intracytoplasmic aggregates, whereas pSynS129 IHC was limited to the detection of mature Lewy body/neurite pathology. Lastly, we could demonstrate that our dual PLA approach also can be applied to detect co-aggregates of pSyn-pTau.

  • 13.
    Behere, Anish
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Thörnqvist, Per-Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Winberg: Behavioral Neuroendocrinology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Winberg: Behavioral Neuroendocrinology.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ekmark-Lewén, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Visualization of early oligomeric α‐synuclein pathology and its impact on the dopaminergic system in the (Thy‐1)‐h[A30P]α‐syn transgenic mouse model2021In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 99, no 10, p. 2525-2539Article in journal (Refereed)
    Abstract [en]

    Aggregation of alpha-synuclein (alpha-syn) into Lewy bodies and Lewy neurites is a pathological hallmark in the Parkinson ' s disease (PD) brain. The formation of alpha-syn oligomers is believed to be an early pathogenic event and the A30P mutation in the gene encoding alpha-syn, causing familial PD, has been shown to cause an accelerated oligomerization. Due to the problem of preserving antigen conformation on tissue surfaces, alpha-syn oligomers are difficult to detect ex vivo using conventional immunohistochemistry with oligomer-selective antibodies. Herein, we have instead employed the previously reported alpha-syn oligomer proximity ligation assay (ASO-PLA), along with a wide variety of biochemical assays, to discern the pathological progression of alpha-syn oligomers and their impact on the dopaminergic system in male and female (Thy-1)-h[A30P]alpha-syn transgenic (A30P-tg) mice. Our results reveal a previously undetected abundance of alpha-syn oligomers in midbrain of young mice, whereas phosphorylated (pS129) and proteinase k-resistant alpha-syn species were observed to a larger extent in aged mice. Although we did not detect loss of dopaminergic neurons in A30P-tg mice, a dysregulation in the monoaminergic system was recorded in older mice. Taken together, ASO-PLA should be a useful method for the detection of early changes in alpha-syn aggregation on brain tissue, from experimental mouse models in addition to post mortem PD cases.

    Download full text (pdf)
    fulltext
  • 14.
    Bellenguez, Celine
    et al.
    Univ Lille, Facteurs Risque & Terminants Mol Malad Liees Viei, Inst Pasteur Lille, INSERM,U1167 RID AGE,CHU Lille, Lille, France.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lambert, Jean-Charles
    Univ Lille, Facteurs Risque & Terminants Mol Malad Liees Viei, Inst Pasteur Lille, INSERM,U1167 RID AGE,CHU Lille, Lille, France.
    New insights into the genetic etiology of Alzheimer's disease and related dementias2022In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 54, no 4, p. 412-436Article in journal (Refereed)
    Abstract [en]

    Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE epsilon 4 allele. Meta-analysis of genome-wide association studies on Alzheimer's disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer's disease and dementia.

    Download full text (pdf)
    FULLTEXT01
  • 15.
    Belloy, Michael E.
    et al.
    Stanford Univ, Dept Neurol & Neurol Sci, Greicius Lab, 290 Jane Stanford Way, Stanford, CA 94304 USA..
    Eger, Sarah J.
    Stanford Univ, Dept Neurol & Neurol Sci, Greicius Lab, 290 Jane Stanford Way, Stanford, CA 94304 USA..
    Le Guen, Yann
    Stanford Univ, Dept Neurol & Neurol Sci, Greicius Lab, 290 Jane Stanford Way, Stanford, CA 94304 USA..
    Damotte, Vincent
    Univ Lille, Inst Pasteur Lille, U1167 RID AGE Facteurs Risque & Determinants Mol, INSERM,CHU Lille, Lille, France..
    Ahmad, Shahzad
    ErasmusMC, Dept Epidemiol, Rotterdam, Netherlands.;Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, Leiden, Netherlands..
    Ikram, M. Arfan
    ErasmusMC, Dept Epidemiol, Rotterdam, Netherlands..
    Ramirez, Alfredo
    Univ Cologne, Fac Med, Dept Psychiat & Psychotherapy, Div Neurogenet & Mol Psychiat, Cologne, Germany.;Univ Cologne, Univ Hosp Cologne, Cologne, Germany.;Univ Hosp Bonn, Med Fac, Dept Neurodegenerat Dis & Geriatr Psychiat, Bonn, Germany.;Dept Psychiat, San Antonio, TX USA.;Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX USA.;German Ctr Neurodegenerat Dis DZNE, Bonn, Germany.;Univ Cologne, Cluster Excellence Cellular Stress Responses Agin, Cologne, Germany..
    Tsolaki, Anthoula C.
    Aristotle Univ Thessaloniki, AHEPA Hosp, Dept Neurol 1, Athens, Greece..
    Rossi, Giacomina
    Fdn IRCCS Ist Neurol Carlo Besta, Unit Neurol 5 & Neuropathol, Milan, Italy..
    Jansen, Iris E.
    Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam UMC,Amsterdam Neurosci, Amsterdam, Netherlands.;Vrije Univ, Ctr Neurogen & Cognit Res, Amsterdam Neurosci, Dept Complex Trait Genet, Amsterdam, Netherlands..
    de Rojas, Itziar
    Univ Int Catalunya, Res Ctr, ACE Alzheimer Ctr Barcelona, Barcelona, Spain.;Univ Int Catalunya, Memory Clin, ACE Alzheimer Ctr Barcelona, Barcelona, Spain.;Inst Salud Carlos III, Networking Res Ctr Neurodegenerat Dis CIBERNED, Madrid, Spain..
    Parveen, Kayenat
    Univ Cologne, Fac Med, Dept Psychiat & Psychotherapy, Div Neurogenet & Mol Psychiat, Cologne, Germany.;Univ Cologne, Univ Hosp Cologne, Cologne, Germany.;Univ Hosp Bonn, Med Fac, Dept Neurodegenerat Dis & Geriatr Psychiat, Bonn, Germany..
    Sleegers, Kristel
    VIB, Ctr Mol Neurol, Complex Genet Alzheimers Dis Grp, Antwerp, Belgium.;Univ Antwerp, Dept Biomed Sci, Antwerp, Belgium..
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hiltunen, Mikko
    Univ Eastern Finland, Inst Biomed, Yliopistonranta 1E, Kuopio 70211, Finland..
    Amin, Najaf
    ErasmusMC, Dept Epidemiol, Rotterdam, Netherlands.;Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England..
    Andreassen, Ole
    Oslo Univ Hosp, NORMENT Ctr, Div Mental Hlth & Addict, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Sánchez-Juan, Pascual
    Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain.;Univ Cantabria, Neurol Serv, Marques de Valdecilla Univ Hosp, Santander, Spain.;IDIVAL, Santander, Spain..
    Kehoe, Patrick
    Univ Bristol, Bristol Med Sch, Translat Hlth Sci, Bristol, Avon, England..
    Amouyel, Philippe
    Univ Lille, Inst Pasteur Lille, U1167 RID AGE Facteurs Risque & Determinants Mol, INSERM,CHU Lille, Lille, France..
    Sims, Rebecca
    Cardiff Univ, Sch Med, Div Psychol Med & Clin Neurosci, Cardiff, S Glam, Wales..
    Frikke-Schmidt, Ruth
    Copenhagen Univ Hosp, Dept Clin Biochem, Rigshosp, Copenhagen, Denmark.;Univ Copenhagen, Dept Clin Med, Copenhagen, Denmark..
    van der Flier, Wiesje M.
    Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam UMC,Amsterdam Neurosci, Amsterdam, Netherlands..
    Lambert, Jean-Charles
    Univ Lille, Inst Pasteur Lille, U1167 RID AGE Facteurs Risque & Determinants Mol, INSERM,CHU Lille, Lille, France..
    He, Zihuai
    Stanford Univ, Dept Neurol & Neurol Sci, Greicius Lab, 290 Jane Stanford Way, Stanford, CA 94304 USA.;Stanford Univ, Dept Med, Quantitat Sci Unit, Stanford, CA 94304 USA..
    Han, Summer S.
    Stanford Univ, Dept Med, Quantitat Sci Unit, Stanford, CA 94304 USA.;Stanford Univ, Dept Neurosurg, Stanford, CA 94304 USA..
    Napolioni, Valerio
    Univ Camerino, Sch Biosci & Vet Med, I-62032 Camerino, Italy..
    Greicius, Michael D.
    Stanford Univ, Dept Neurol & Neurol Sci, Greicius Lab, 290 Jane Stanford Way, Stanford, CA 94304 USA..
    Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping2022In: Alzheimer's Research & Therapy, E-ISSN 1758-9193, Vol. 14, no 1, article id 22Article in journal (Refereed)
    Abstract [en]

    Background: Genetic variants within the APOE locus may modulate Alzheimer's disease (AD) risk independently or in conjunction with APOE*2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE*2/3/4 genotype quality. Here, we present a novel APOE*2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE.

    Methods: We used thirty-two AD-related cohorts, with genetic data from various high-density single-nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n = 65,701). Primary analyses investigated AD risk in APOE*4/4 carriers. Additional supporting analyses were performed in APOE*3/4 and 3/3 strata. Outcomes were compared under two different APOE*2/3/4 filtering approaches.

    Results: Using more conventional APOE*2/3/4 filtering criteria (approach 1), we showed that, when in-phase with APOE*4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases the certainty of the APOE*2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost.

    Conclusions: We showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE*2/3/4.

    Download full text (pdf)
    FULLTEXT01
  • 16.
    Beretta, Chiara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nikitidou, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gallasch, Linn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Extracellular vesicles from amyloid-beta exposed cell cultures induce severe dysfunction in cortical neurons2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, article id 19656Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is characterized by a substantial loss of neurons and synapses throughout the brain. The exact mechanism behind the neurodegeneration is still unclear, but recent data suggests that spreading of amyloid-beta (A beta) pathology via extracellular vesicles (EVs) may contribute to disease progression. We have previously shown that an incomplete degradation of A beta (42) protofibrils by astrocytes results in the release of EVs containing neurotoxic A beta. Here, we describe the cellular mechanisms behind EV-associated neurotoxicity in detail. EVs were isolated from untreated and A beta (42) protofibril exposed neuroglial co-cultures, consisting mainly of astrocytes. The EVs were added to cortical neurons for 2 or 4 days and the neurodegenerative processes were followed with immunocytochemistry, time-lapse imaging and transmission electron microscopy (TEM). Addition of EVs from A beta (42) protofibril exposed co-cultures resulted in synaptic loss, severe mitochondrial impairment and apoptosis. TEM analysis demonstrated that the EVs induced axonal swelling and vacuolization of the neuronal cell bodies. Interestingly, EV exposed neurons also displayed pathological lamellar bodies of cholesterol deposits in lysosomal compartments. Taken together, our data show that the secretion of EVs from A beta exposed cells induces neuronal dysfunction in several ways, indicating a central role for EVs in the progression of A beta -induced pathology.

    Download full text (pdf)
    FULLTEXT01
  • 17.
    Bergström, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Näsström, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Wahlberg, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Karlsson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Nikolajeff, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Effects of lipid peroxidation metabolites on alpha-synuclein aggregation2009Conference paper (Refereed)
  • 18.
    Bergström, Sofia
    et al.
    Division of Affinity Proteomics Department of Protein Science SciLifeLab KTH Royal Institute of Technology Stockholm Sweden.
    Remnestål, Julia
    Division of Affinity Proteomics Department of Protein Science SciLifeLab KTH Royal Institute of Technology Stockholm Sweden.
    Yousef, Jamil
    Division of Affinity Proteomics Department of Protein Science SciLifeLab KTH Royal Institute of Technology Stockholm Sweden.
    Olofsson, Jennie
    Division of Affinity Proteomics Department of Protein Science SciLifeLab KTH Royal Institute of Technology Stockholm Sweden.
    Markaki, Ioanna
    Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden.
    Carvalho, Stephanie
    Sorbonne Université Institut du Cerveau ‐ Paris Brain Institute ‐ ICM, Assistance‐Publique Hôpitaux de Paris INSERM CNRS Hôpital Pitié‐Salpêtrière Department of Neurology Centre d’Investigation Clinique Neurosciences Paris France.
    Corvol, Jean‐Christophe
    Sorbonne Université Institut du Cerveau ‐ Paris Brain Institute ‐ ICM, Assistance‐Publique Hôpitaux de Paris INSERM CNRS Hôpital Pitié‐Salpêtrière Department of Neurology Centre d’Investigation Clinique Neurosciences Paris France.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Löwenmark, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Blennow, Kaj
    Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology The Sahlgrenska Academy University of Gothenburg;Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden.
    Zetterberg, Henrik
    Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology The Sahlgrenska Academy University of Gothenburg;Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden;Department of Neurodegenerative Disease UCL Institute of Neurology London UK;UK Dementia Research Institute at UCL London UK.
    Nellgård, Bengt
    Anesthesiology and Intensive Care Medicine Sahlgrenska University Hospital Mölndal Sweden;Department of Anesthesiology and Intensive Care Medicine Institute of Clinical Sciences The Sahlgrenska Academy University of Gothenburg.
    Brosseron, Frederic
    Universitätsklinikum Bonn Germany;German Center for Neurodegenerative Diseases (DZNE) Bonn Germany.
    Heneka, Michael T.
    Universitätsklinikum Bonn Germany.
    Bosch, Beatriz
    Alzheimer’s and other cognitive disorders Unit. Service of Neurology Hospital Clínic de Barcelona Institut d'Investigació Biomèdica August Pi i Sunyer University of Barcelona Barcelona Spain.
    Sanchez‐Valle, Raquel
    Alzheimer’s and other cognitive disorders Unit. Service of Neurology Hospital Clínic de Barcelona Institut d'Investigació Biomèdica August Pi i Sunyer University of Barcelona Barcelona Spain.
    Månberg, Anna
    Division of Affinity Proteomics Department of Protein Science SciLifeLab KTH Royal Institute of Technology Stockholm Sweden.
    Svenningsson, Per
    Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden.
    Nilsson, Peter
    Division of Affinity Proteomics Department of Protein Science SciLifeLab KTH Royal Institute of Technology Stockholm Sweden.
    Multi‐cohort profiling reveals elevated CSF levels of brain‐enriched proteins in Alzheimer’s disease2021In: Annals of Clinical and Translational Neurology, E-ISSN 2328-9503, Vol. 8, no 7, p. 1456-1470Article in journal (Refereed)
    Abstract [en]

    Objective: Decreased amyloid beta (Aβ) 42 together with increased tau and phospho-tau in cerebrospinal fluid (CSF) is indicative of Alzheimer’s disease (AD). However, the molecular pathophysiology underlying the slowly progressive cognitive decline observed in AD is not fully understood and it is not known what other CSF biomarkers may be altered in early disease stages.

    Methods: We utilized an antibody-based suspension bead array to analyze levels of 216 proteins in CSF from AD patients, patients with mild cognitive impairment (MCI), and controls from two independent cohorts collected within the AETIONOMY consortium. Two additional cohorts from Sweden were used for biological verification.

    Results: Six proteins, amphiphysin (AMPH), aquaporin 4 (AQP4), cAMP-regulated phosphoprotein 21 (ARPP21), growth-associated protein 43 (GAP43), neurofilament medium polypeptide (NEFM), and synuclein beta (SNCB) were found at increased levels in CSF from AD patients compared with controls. Next, we used CSF levels of Aβ42 and tau for the stratification of the MCI patients and observed increased levels of AMPH, AQP4, ARPP21, GAP43, and SNCB in the MCI subgroups with abnormal tau levels compared with controls. Further characterization revealed strong to moderate correlations between these five proteins and tau concentrations.

    Interpretations: In conclusion, we report six extensively replicated candidate biomarkers with the potential to reflect disease development. Continued evaluation of these proteins will determine to what extent they can aid in the discrimination of MCI patients with and without an underlying AD etiology, and if they have the potential to contribute to a better understanding of the AD continuum.

    Download full text (pdf)
    fulltext
  • 19. Bertram, Lars
    et al.
    Schjeide, Brit-Maren M.
    Hooli, Basavaraj
    Mullin, Kristina
    Hiltunen, Mikko
    Soininen, Hilkka
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Blacker, Deborah
    Tanzi, Rudolph E.
    No association between CALHM1 and Alzheimer's disease risk2008In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 135, no 6, p. 993-994Article in journal (Refereed)
  • 20. Beyer, Anja-Silke
    et al.
    von Einem, Bjoern
    Schwanzar, Daniel
    Keller, Ilona E
    Hellrung, Anke
    Thal, Dietmar R
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Makarova, Alexandra
    Deng, Meihua
    Chhabra, Ekta S
    Pröpper, Christian
    Böckers, Tobias M
    Hyman, Bradley T
    von Arnim, Christine A F
    Engulfment adapter PTB domain containing 1 interacts with and affects processing of the amyloid-beta precursor protein2010In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 4, p. 732-743Article in journal (Refereed)
    Abstract [en]

    Previous studies identified engulfment adapter phosphotyrosine binding (PTB) domain containing 1 (GULP1) as an NPXY-motif interactor of low-density lipoprotein receptor-related protein 1 (LRP1) and suggested a potential relevance in Alzheimer's disease (AD). Since AD associated proteins amyloid-beta A4 precursor protein (APP) and LRP1 were shown to interact with the PTB domain of Fe65 and several other adapters via their intracellular NPXY-motifs, we examined a possible interaction of GULP1 PTB domain with the YENPTY-motif of APP. Here we demonstrate that GULP1 is present in human hippocampal and neocortical neurons. Confocal live cell imaging revealed that coexpressed and endogenous GULP1 colocalizes with APP in the Golgi and endoplasmic reticulum. Analysis of the interacting domains by co-immunoprecipitation of point and deletion mutants revealed that the interaction depends on the PTB domain of GULP1 and the YENPTY-motif of APP. Coexpression of GULP1 affected APP cell surface localization and suppressed generation of Abeta40/42 and sAPPalpha. Taken together, these data identify GULP1 as a novel neuronal APP interacting protein that alters trafficking and processing of APP.

  • 21.
    Björkesten, Johan
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Shen, Qiujin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wik, Lotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hougaard, David
    Statens Serum Inst, Danish Ctr Neonatal Screening, Copenhagen, Denmark.
    Cohen, Arieh
    Statens Serum Inst, Danish Ctr Neonatal Screening, Copenhagen, Denmark.
    Sörensen, Lene
    Karolinska Univ Hosp, Ctr Inherited Metab Dis, Stockholm, Sweden.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stability of Proteins in Dried Blood Spot Biobanks.2017In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 16, no 7, p. 1286-1296Article in journal (Refereed)
    Abstract [en]

    An important motivation for the construction of biobanks is to discover biomarkers that identify diseases at early, potentially curable stages. This will require biobanks from large numbers of individuals, preferably sampled repeatedly, where the samples are collected and stored under conditions that preserve potential biomarkers. Dried blood samples are attractive for biobanking because of the ease and low cost of collection and storage. Here we have investigated their suitability for protein measurements. 92 proteins with relevance for oncology were analyzed using multiplex proximity extension assays (PEA) in dried blood spots collected on paper and stored for up to 30 years at either +4&deg;C or -24&deg;C.</p> <p>Our main findings were that 1) the act of drying only slightly influenced detection of blood proteins (average correlation of 0.970), and in a reproducible manner (correlation of 0.999), 2) detection of some proteins was not significantly affected by storage over the full range of three decades (34% and 76% of the analyzed proteins at +4&deg;C and -24&deg;C, respectively), while levels of others decreased slowly during storage with half-lives in the range of 10 to 50 years, and 3) detectability of proteins was less affected in dried samples stored at -24&deg;C compared to at +4&deg;C, as the median protein abundance had decreased to 80% and 93% of starting levels after 10 years of storage at +4&deg;C or -24&deg;C, respectively. The results of our study are encouraging as they suggest an inexpensive means to collect large numbers of blood samples, even by the donors themselves, and to transport, and store biobanked samples as spots of whole blood dried on paper. Combined with emerging means to measure hundreds or thousands of protein, such biobanks could prove of great medical value by greatly enhancing discovery as well as routine analysis of blood biomarkers.

    Download full text (pdf)
    fulltext
  • 22.
    Blom, Elin S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Zetterberg, Henrik
    Fukumoto, Hiroaki
    Blennow, Kaj
    Hyman, Bradley T.
    Irizarry, Michael C.
    Wahlund, Lars-Olof
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Rapid progression from mild cognitive impairment to Alzheimer's disease in subjects with elevated levels of tau in cerebrospinal fluid and the APOE epsilon4/epsilon4 genotype2009In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 27, no 5, p. 458-464Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/AIMS: Increased cerebrospinal fluid (CSF) tau, decreased CSF amyloid-beta42 (Abeta42) and the apolipoprotein E gene (APOE) epsilon4 allele predict progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Here, we investigated these markers to assess their predictive value and influence on the rate of disease progression. METHODS: Using ELISA, we measured the CSF biomarkers in 47 AD patients, 58 patients with MCI and 35 healthy control subjects. Twenty-eight MCI patients revisited the clinic and half of them progressed to AD during a period of 3-12 years. RESULTS: The expected changes in CSF total (T)-tau, phosphorylated (P)-tau and Abeta42 levels were found in AD, confirming the diagnostic value of these biomarkers. We were also able to corroborate an increased risk for progression from MCI to AD with elevated CSF T-tau and P-tau and with the presence of the APOE epsilon4/epsilon4 genotype, but not with decreased Abeta42. Finally, for the first time we demonstrated that MCI subjects with high CSF T-tau or P-tau and APOE epsilon4 homozygosity progressed faster from MCI to AD. CONCLUSIONS: CSF T-tau and P-tau as well as the APOE epsilon4/epsilon4 genotype are robust predictors of AD and are also associated with a more rapid progression from MCI to AD.

  • 23.
    Blom, Elin S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Wang, Yijing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Skoglund, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Hansson, Anita C
    Ubaldi, Massimo
    Lourdusamy, Anbarasu
    Sommer, Wolfgang H
    Mielke, Matthew
    Hyman, Bradley T
    Heilig, Markus
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Nilsson, Lars N G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Increased mRNA Levels of TCF7L2 and MYC of the Wnt Pathway in Tg-ArcSwe Mice and Alzheimer's Disease Brain2010In: International journal of Alzheimer's disease, ISSN 2090-0252, Vol. 2011, p. 936580-Article in journal (Refereed)
    Abstract [en]

    Several components in the Wnt pathway, including β-catenin and glycogen synthase kinase 3 beta, have been implied in AD pathogenesis. Here, mRNA brain levels from five-month-old tg-ArcSwe and nontransgenic mice were compared using Affymetrix microarray analysis. With surprisingly small overall changes, Wnt signaling was the most affected pathway with altered expression of nine genes in tg-ArcSwe mice. When analyzing mRNA levels of these genes in human brain, transcription factor 7-like 2 (TCF7L2) and v-myc myelocytomatosis viral oncogene homolog (MYC), were increased in Alzheimer's disease (AD) (P < .05). Furthermore, no clear differences in TCF7L2 and MYC mRNA were found in brains with frontotemporal lobar degeneration, suggesting that altered regulation of these Wnt-related genes could be specific to AD. Finally, mRNA levels of three neurogenesis markers were analyzed. Increased mRNA levels of dihydropyrimidinase-like 3 were observed in AD brain, suggesting that altered Wnt pathway regulation may signify synaptic rearrangement or neurogenesis.

  • 24.
    Boström, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Virhammar, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Alcolea, Daniel
    Hosp Santa Creu & Sant Pau, Neurol Dept, Memory Unit, Barcelona, Spain.;Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain..
    Tumani, Hayrettin
    Ulm Univ Hosp, Dept Neurol, Ulm, Germany..
    Otto, Markus
    Ulm Univ Hosp, Dept Neurol, Ulm, Germany..
    Brundin, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Löwenmark, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lleo, Alberto
    Hosp Santa Creu & Sant Pau, Neurol Dept, Memory Unit, Barcelona, Spain.;Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain..
    von Arnim, Christine A. F.
    Ulm Univ Hosp, Dept Neurol, Ulm, Germany.;Georg August Univ, Univ Med Ctr Gottingen, Dept Geriatr Med, Gottingen, Germany..
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Different Inflammatory Signatures in Alzheimer's Disease and Frontotemporal Dementia Cerebrospinal Fluid2021In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 81, no 2, p. 629-640Article in journal (Refereed)
    Abstract [en]

    Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases.

    Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD.

    Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing.

    Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14-1.53, q = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20-1.94, q = 0.045; and FTD: FC = 1.42, 95% CI 1.10-1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05).

    Conclusion: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.

    Download full text (pdf)
    fulltext
  • 25.
    Braun, Madelen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurology.
    Boström, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics. Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada.;Univ Toronto, Dept Med, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada.;Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada..
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Löwenmark, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurology.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurology.
    Niemelä, Valter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurology.
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Virhammar, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurology.
    Levels of inflammatory cytokines MCP-1, CCL4, and PD-L1 in CSF differentiate idiopathic normal pressure hydrocephalus from neurodegenerative diseases2023In: Fluids and Barriers of the CNS, E-ISSN 2045-8118, Vol. 20, article id 72Article in journal (Refereed)
    Abstract [en]

    Background: Neuroinflammatory processes have been suggested to play a role in the pathophysiology of neurodegenerative diseases and post-hemorrhagic hydrocephalus, but have rarely been investigated in patients with idiopathic normal pressure hydrocephalus (iNPH). The aim of this study was to investigate whether levels of inflammatory proteins in CSF are different in iNPH compared to healthy controls and patients with selected neurodegenerative disorders, and whether any of these markers can aid in the differential diagnosis of iNPH.

    Methods: Lumbar CSF was collected from 172 patients from a single center and represented iNPH (n = 74), Alzheimer's disease (AD) (n = 21), mild cognitive impairment (MCI) due to AD (n = 21), stable MCI (n = 22), frontotemporal dementia (n = 13), and healthy controls (HC) (n = 21). Levels of 92 inflammatory proteins were analyzed using a proximity extension assay. As a first step, differences between iNPH and HC were investigated, and proteins that differed between iNPH and HC were then compared with those from the other groups. The linear regressions were adjusted for age, sex, and plate number.

    Results: Three proteins showed higher (MCP-1, p = 0.0013; CCL4, p = 0.0008; CCL11, p = 0.0022) and one lower (PD-L1, p = 0.0051) levels in patients with iNPH compared to HC. MCP-1 was then found to be higher in iNPH than in all other groups. CCL4 was higher in iNPH than in all other groups, except in MCI due to AD. PD-L1 was lower in iNPH compared to all other groups, except in stable MCI. Levels of CCL11 did not differ between iNPH and the differential diagnoses. In a model based on the four proteins mentioned above, the mean area under the receiver operating characteristic curve used to discriminate between iNPH and the other disorders was 0.91.

    Conclusions: The inflammatory cytokines MCP-1 and CCL4 are present at higher-and PD-L1 at lower-levels in iNPH than in the other investigated diagnoses. These three selected cytokines may have diagnostic potential in the work-up of patients with iNPH.

    Download full text (pdf)
    FULLTEXT01
  • 26.
    Brolin, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Almandoz-Gil, Leire
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Rofo, Fadi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ekmark-Lewén, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hyman, Bradley T.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Alpha-synuclein aggregates affect the distribution of SNARE complex proteins in synapses of A30P alpha-synuclein transgenic mice and Parkinson´s disease brainManuscript (preprint) (Other academic)
  • 27.
    Brolin, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada.;Univ Toronto, Dept Med, Toronto, ON, Canada.;Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Altered Distribution of SNARE Proteins in Primary Neurons Exposed to Different Alpha-Synuclein Proteoforms2023In: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 43, no 6, p. 3023-3035Article in journal (Refereed)
    Abstract [en]

    Growing evidence indicates that the pathological alpha-synuclein (a-syn) aggregation in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) starts at the synapses. Physiologic a-syn is involved in regulating neurotransmitter release by binding to the SNARE complex protein VAMP-2 on synaptic vesicles. However, in which way the SNARE complex formation is affected by a-syn pathology remains unclear. In this study, primary cortical neurons were exposed to either a-syn monomers or preformed fibrils (PFFs) for different time points and the effect on SNARE protein distribution was analyzed with a novel proximity ligation assay (PLA). Short-term exposure to monomers or PFFs for 24 h increased the co-localization of VAMP-2 and syntaxin-1, but reduced the co-localization of SNAP-25 and syntaxin-1, indicating a direct effect of the added a-syn on SNARE protein distribution. Long-term exposure to a-syn PFFs for 7 d reduced VAMP-2 and SNAP-25 co-localization, although there was only a modest induction of ser129 phosphorylated (pS129) a-syn. Similarly, exposure to extracellular vesicles collected from astrocytes treated with a-syn PFFs for 7 d influenced VAMP-2 and SNAP-25 co-localization despite only low levels of pS129 a-syn being formed. Taken together, our results demonstrate that different a-syn proteoforms have the potential to alter the distribution of SNARE proteins at the synapse.

    Download full text (pdf)
    FULLTEXT01
  • 28.
    Cai, Yixiao
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Lendel, Christofer
    Österlund, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Kasrayan, Alex
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nikolajeff, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Karlsson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Changes in secondary structure of α-synuclein during oligomerization induced by reactive aldehydes.2015In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 464, no 1, p. 336-341Article in journal (Refereed)
    Abstract [en]

    The oxidative stress-related reactive aldehydes 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) have been shown to promote formation of α-synuclein oligomers in vitro. However, the changes in secondary structure of α-synuclein and the kinetics of the oligomerization process are not known and were the focus of this study. Size exclusion chromatography showed that after 1 h of incubation, HNE induced the formation of an oligomeric α-synuclein peak with a molecular weight of about ∼2000 kDa, which coincided with a decreasing ∼50 kDa monomeric peak. With prolonged incubation (up to 24 h) the oligomeric peak became the dominating molecular species. In contrast, in the presence of ONE, a ∼2000 oligomeric peak was exclusively observed after 15 min of incubation and this peak remained constant with prolonged incubation. Western blot analysis of HNE-induced α-synuclein oligomers showed the presence of monomers (15 kDa), SDS-resistant low molecular (30-160 kDa) and high molecular weight oligomers (≥260 kDa), indicating that the oligomers consisted of both covalent and non-covalent protein. In contrast, ONE-induced α-synuclein oligomers only migrated as covalent cross-linked high molecular-weight material (≥300 kDa). Both circular dichroism (CD) and Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy showed that the formation of HNE- and ONE-induced oligomers coincided with a spectral change from random coil to β-sheet. However, ONE-induced α-synuclein oligomers exhibited a slightly higher degree of β-sheet. Taken together, our results indicate that both HNE and ONE induce a change from random coil to β-sheet structure that coincides with the formation of α-synuclein oligomers. Albeit through different kinetic pathways depending on the degree of cross-linking.

  • 29.
    Carolina Dalmasso, Maria
    et al.
    Consejo Nacl Invest Cient & Tecn, IIBBA, Fdn Inst Leloir, Lab Amyloidosis & Neurodegenerat,CABA, Buenos Aires, DF, Argentina.
    Ignacio Brusco, Luis
    UBA, Fac Med, Ctr Neuropsiquiatria Neurol Conducta CENFCON, CABA, Buenos Aires, DF, Argentina;UBA, CABA, Fac Med, Dept Ciencias Fisiol UAII, Buenos Aires, DF, Argentina;Hosp Interzonal Gen Agudos Eva Peron, Buenos Aires, DF, Argentina.
    Olivar, Natividad
    UBA, Fac Med, Ctr Neuropsiquiatria Neurol Conducta CENFCON, CABA, Buenos Aires, DF, Argentina;UBA, CABA, Fac Med, Dept Ciencias Fisiol UAII, Buenos Aires, DF, Argentina.
    Muchnik, Carolina
    UBA, CABA, Inst Invest Med Lanari, Lab Bioquim Mol,Fac Med, Buenos Aires, DF, Argentina.
    Hanses, Claudia
    Univ Bonn, Dept Psychiat & Psychotherapy, D-53127 Bonn, Germany.
    Milz, Esther
    Univ Cologne, Dept Psychiat Psychotherapy, Div Neurogenet & Mol Psychiat, D-50937 Cologne, Germany.
    Becker, Julian
    Univ Bonn, Dept Psychiat & Psychotherapy, D-53127 Bonn, Germany.
    Heilmann-Heimbach, Stefanie
    Univ Bonn, Sch Med, Inst Human Genet, D-53127 Bonn, Germany;Univ Hosp, D-53127 Bonn, Germany;Univ Bonn, Life & Brain Ctr, Dept Genom, D-53127 Bonn, Germany.
    Hoffmann, Per
    Univ Bonn, Sch Med, Inst Human Genet, D-53127 Bonn, Germany;Univ Hosp, D-53127 Bonn, Germany;Univ Bonn, Life & Brain Ctr, Dept Genom, D-53127 Bonn, Germany;Univ Basel, Univ Hosp, Div Med Genet, CH-4058 Basel, Switzerland;Univ Basel, Dept Biomed, CH-4058 Basel, Switzerland.
    Prestia, Federico A.
    Consejo Nacl Invest Cient & Tecn, IIBBA, Fdn Inst Leloir, Lab Amyloidosis & Neurodegenerat,CABA, Buenos Aires, DF, Argentina.
    Galeano, Pablo
    Consejo Nacl Invest Cient & Tecn, IIBBA, Fdn Inst Leloir, Lab Amyloidosis & Neurodegenerat,CABA, Buenos Aires, DF, Argentina.
    Sanchez Avalos, Mariana Soledad
    Programa Adulto Mayor, Minist Salud Provi Jujuy, San Salvador De Jujuy, Jujuy, Argentina.
    Eduardo Martinez, Luis
    Hosp Interzonal Gen Agudos Eva Peron, Buenos Aires, DF, Argentina.
    Estela Carulla, Mariana
    Hosp Interzonal Gen Agudos Eva Peron, Buenos Aires, DF, Argentina.
    Javier Azurmendi, Pablo
    UBA, CABA, Inst Invest Med Lanari, Lab Bioquim Mol,Fac Med, Buenos Aires, DF, Argentina.
    Liberczuk, Cynthia
    UBA, Fac Med, Ctr Neuropsiquiatria Neurol Conducta CENFCON, CABA, Buenos Aires, DF, Argentina.
    Fezza, Cristina
    UBA, CABA, Inst Invest Med Lanari, Lab Bioquim Mol,Fac Med, Buenos Aires, DF, Argentina.
    Sampano, Marcelo
    UBA, Fac Med, Ctr Neuropsiquiatria Neurol Conducta CENFCON, CABA, Buenos Aires, DF, Argentina.
    Fierens, Maria
    UBA, Fac Med, Ctr Neuropsiquiatria Neurol Conducta CENFCON, CABA, Buenos Aires, DF, Argentina.
    Jemar, Guillermo
    UBA, Fac Med, Ctr Neuropsiquiatria Neurol Conducta CENFCON, CABA, Buenos Aires, DF, Argentina.
    Solis, Patricia
    Univ Arturo Jauretche, Hosp El Cruce Dr Nestor Kirchner, CONICET, Neurosci & Complex Syst Unit EnyS, Buenos Aires, DF, Argentina.
    Medel, Nancy
    Univ Arturo Jauretche, Hosp El Cruce Dr Nestor Kirchner, CONICET, Neurosci & Complex Syst Unit EnyS, Buenos Aires, DF, Argentina.
    Lisso, Julieta
    Univ Arturo Jauretche, Hosp El Cruce Dr Nestor Kirchner, CONICET, Neurosci & Complex Syst Unit EnyS, Buenos Aires, DF, Argentina.
    Sevillano, Zulma
    Univ Arturo Jauretche, Hosp El Cruce Dr Nestor Kirchner, CONICET, Neurosci & Complex Syst Unit EnyS, Buenos Aires, DF, Argentina.
    Bosco, Paolo
    Inst Ricovero Cura Carattere Sci IRCCS, Assoc Oasi Maria Santissima Srl, Troina, Italy.
    Bossu, Paola
    Spalletta, Gianfranco
    IRCCS Santa Lucia Fdn, Neuropsychiat Lab, Dept Clin & Behav Neurol, Rome, Italy.
    Galimberti, Daniela
    Univ Milan, IRCCS Osped Maggiore Policlin, Fdn Ca Granda, Neurodegenerat Dis Ctr,Ctr Dino Ferrari, Milan, Italy.
    Mancuso, Michelangelo
    Univ Pisa, Neurol Inst, Dept Expt & Clin Med, Pisa, Italy.
    Nacmias, Benedetta
    Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Dept Neurosci, NEUROFARBA, Florence, Italy.
    Sorbi, Sandro
    Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Dept Neurosci, NEUROFARBA, Florence, Italy;IRCCS Don Carlo Gnocchi, Florence, Italy.
    Mecocci, Patrizia
    Univ Perugia, Dept Med, Sect Gerontol & Geriatr, Perugia, Italy.
    Pilotto, Alberto
    IRCCS Casa Sollievo Sofferenza, Dept Med Sci, Geriatr Unit, San Giovanni Rotondo, Italy;IRCCS Casa Sollievo Sofferenza, Dept Med Sci, Gerontol Geriatr Res Lab, San Giovanni Rotondo, Italy.
    Caffarra, Paolo
    Univ Parma, DIMEC, Sect Neurosci, Parma, Italy;FERB, Alzheimer Ctr, Bergamo, Italy.
    Panza, Francesco
    Univ Bari Aldo Moro, Dept Basic Med Neurosci & Sense Organs, Neurodegenerat Dis Unit, Bari, Italy.
    Bullido, Maria
    Hosp Paz IdiPAZ, Inst Invest Sanitaria, Madrid, Spain;Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain;UAM, CSIC, Ctr Biol Mol Severo Ochoa, Madrid, Spain.
    Clarimon, Jordi
    Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain;Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst, Memory Unit,Neurol Dept & Sant Pau, Barcelona, Spain.
    Sanchez-Juan, Pascual
    Univ Cantabria, Marques Valdecilla Univ Hosp, Neurol Serv, Santander, Spain;Univ Cantabria, CIBERNED, Marques Valdecilla Univ Hosp, Santander, Spain;IDIVAL, Santander, Spain.
    Coto, Eliecer
    Univ Cent Asturias, Mol Genet Lab Hosp, Oviedo, Spain.
    Sanchez-Garcia, Florentino
    Hosp Univ Gran Canaria Doctor Negrin, Immunol Serv, Las Palmas Gran Canaria, Spain.
    Graff, Caroline
    Karolinska Univ Hosp, Theme Aging, Genet Unit, Solna, Sweden;Karolinska Inst, Dept NVS, Div Neurogeriatr, Bioclin J10-20, Solna, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bellenguez, Celine
    INSERM, U1167, RID AGE Risk Factors & Mol Determinants Aging Rel, F-59000 Lille, France;Inst Pasteur, F-59000 Lille, France;Univ Lille, U1167, Excellence Lab LabEx DISTALZ, F-59000 Lille, France.
    Miguel Castano, Eduardo
    Consejo Nacl Invest Cient & Tecn, IIBBA, Fdn Inst Leloir, Lab Amyloidosis & Neurodegenerat,CABA, Buenos Aires, DF, Argentina.
    Kairiyama, Claudia
    Hosp Interzonal Gen Agudos Eva Peron, Buenos Aires, DF, Argentina.
    Gustavo Politis, Daniel
    Hosp Interzonal Gen Agudos Eva Peron, Buenos Aires, DF, Argentina.
    Kochen, Silvia
    Univ Arturo Jauretche, Hosp El Cruce Dr Nestor Kirchner, CONICET, Neurosci & Complex Syst Unit EnyS, Buenos Aires, DF, Argentina.
    Scaro, Horacio
    Programa Adulto Mayor, Minist Salud Provi Jujuy, San Salvador De Jujuy, Jujuy, Argentina.
    Maier, Wolfgang
    German Ctr Neurodegenerat Dis DZNE, D-53127 Bonn, Germany;Univ Bonn, Dept Neurodegenerat Dis & Geriatr Psychiat, D-53127 Bonn, Germany.
    Jessen, Frank
    German Ctr Neurodegenerat Dis DZNE, D-53127 Bonn, Germany;Univ Cologne, Dept Psychiat & Psychotherapy, D-50937 Cologne, Germany.
    Alberto Mangone, Carlos
    UBA, Fac Med, Ctr Neuropsiquiatria Neurol Conducta CENFCON, CABA, Buenos Aires, DF, Argentina.
    Lambert, Jean-Charles
    INSERM, U1167, RID AGE Risk Factors & Mol Determinants Aging Rel, F-59000 Lille, France;Inst Pasteur, F-59000 Lille, France;Univ Lille, U1167, Excellence Lab LabEx DISTALZ, F-59000 Lille, France.
    Morelli, Laura
    Consejo Nacl Invest Cient & Tecn, IIBBA, Fdn Inst Leloir, Lab Amyloidosis & Neurodegenerat,CABA, Buenos Aires, DF, Argentina.
    Ramirez, Alfredo
    Univ Cologne, Dept Psychiat Psychotherapy, Div Neurogenet & Mol Psychiat, D-50937 Cologne, Germany;Univ Bonn, Dept Neurodegenerat Dis & Geriatr Psychiat, D-53127 Bonn, Germany.
    Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, article id 55Article in journal (Refereed)
    Abstract [en]

    Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.

    Download full text (pdf)
    FULLTEXT01
  • 30.
    Cedervall, Ylva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Stenberg, Anna M.
    Åhman, Hanna Bozkurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Tinmark, Fredrik
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Halvorsen, Kjartan
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control. Department of Mechatronics, Campus Estado de Mexico, Tecnologico de Monterrey, Monterrey 64849, NL, Mexiko..
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Rosendahl, Erik
    Åberg, Anna Cristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Dalarna Univ, Sch Educ Hlth & Social Studies, SE-79188 Falun, Sweden..
    Timed Up-and-Go Dual-Task Testing in the Assessment of Cognitive Function: A Mixed Methods Observational Study for Development of the UDDGait Protocol2020In: International Journal of Environmental Research and Public Health, ISSN 1661-7827, E-ISSN 1660-4601, Vol. 17, no 5, article id 1715Article in journal (Refereed)
    Abstract [en]

    New methods to screen for and identify early-stage dementia disorders are highly sought after. The purpose of this pilot study is to develop a study protocol for a dual-task test aimed at aiding the early detection of dementia disorders. We used the Timed Up-and-Go (TUG) test, which is a mobility task involving starting in a sitting position, standing up, walking three meters to cross a line on the floor, turning around, walking back and sitting down again. We combined TUG with the verbal task of naming different animals. Pilot study participants were 43 individuals with and without established dementia diagnoses who attended a clinic for memory assessment. Video-recorded test performances were systematically analysed. Deviant test performances concerning the interplay between test administration and participants' responses to the assessment instructions were revealed and led to refinements being made to the final study protocol. Exploration of the dual-task test outcome measures in a sub-sample of 22 persons, ten with and twelve without dementia, indicated that step-length and number of named animals after the turning point of the dual-task test might constitute appropriate measures for examining this kind of sample. We concluded that the refined study protocol is feasible for testing individuals undergoing initial memory assessments and healthy controls. Follow-up studies with larger samples are being carried out and will bring new knowledge to this area of research. It may also provide an opportunity for further studies exploring possibilities for broad clinical implementation.

    Download full text (pdf)
    fulltext
  • 31.
    Condello, Carlo
    et al.
    Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.;Univ Calif San Francisco, Weill Inst Neurosci, Dept Neurol, San Francisco, CA 94158 USA..
    Lemmin, Thomas
    Univ Calif San Francisco, Cardiovasc Res Inst, Dept Pharmaceut Chem, San Francisco, CA 94158 USA..
    Stöhr, Jan
    Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.;Univ Calif San Francisco, Weill Inst Neurosci, Dept Neurol, San Francisco, CA 94158 USA..
    Nick, Mimi
    Univ Calif San Francisco, Cardiovasc Res Inst, Dept Pharmaceut Chem, San Francisco, CA 94158 USA..
    Wu, Yibing
    Univ Calif San Francisco, Cardiovasc Res Inst, Dept Pharmaceut Chem, San Francisco, CA 94158 USA..
    Maxwell, Alison M.
    Univ Calif San Francisco, Cardiovasc Res Inst, Dept Pharmaceut Chem, San Francisco, CA 94158 USA..
    Watts, Joel C.
    Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Dept Biochem, Toronto, ON MST 258, Canada..
    Caro, Christoffer D.
    Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA..
    Oehler, Abby
    Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA..
    Keene, C. Dirk
    Univ Washington, Dept Pathol, Seattle, WA 98195 USA..
    Bird, Thomas D.
    VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA.;Univ Washington, Dept Neurol, Seattle, WA 98195 USA..
    van Duinen, Sjoerd G.
    Leiden Univ, Med Ctr, Dept Pathol, NL-2333 ZA Leiden, Netherlands..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Graff, Caroline
    Karolinska Inst, Div Neurogeriatr, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, S-14157 Huddinge, Sweden.;Karolinska Univ Hosp Huddinge, Dept Geriatr Med, S-14186 Stockholm, Sweden..
    Giles, Kurt
    Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.;Univ Calif San Francisco, Weill Inst Neurosci, Dept Neurol, San Francisco, CA 94158 USA..
    DeGrado, William F.
    Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.;Univ Calif San Francisco, Cardiovasc Res Inst, Dept Pharmaceut Chem, San Francisco, CA 94158 USA..
    Prusiner, Stanley B.
    Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.;Univ Calif San Francisco, Weill Inst Neurosci, Dept Neurol, San Francisco, CA 94158 USA.;Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA..
    Structural heterogeneity and intersubject variability of A beta in familial and sporadic Alzheimer's disease2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 4, p. E782-E791Article in journal (Refereed)
    Abstract [en]

    Point mutations in the amyloid-beta (A beta) coding region produce a combination of mutant and WT A beta isoforms that yield unique clinicopathologies in familial Alzheimer's disease (fAD) and cerebral amyloid angiopathy (fCAA) patients. Here, we report a method to investigate the structural variability of amyloid deposits found in fAD, fCAA, and sporadic AD (sAD). Using this approach, we demonstrate that mutant A beta determines WT A beta conformation through prion template-directed misfolding. Using principal component analysis of multiple structure-sensitive fluorescent amyloid-binding dyes, we assessed the conformational variability of A beta deposits in fAD, fCAA, and sAD patients. Comparing many deposits from a given patient with the overall population, we found that intrapatient variability is much lower than interpatient variability for both disease types. In a given brain, we observed one or two structurally distinct forms. When two forms coexist, they segregate between the parenchyma and cerebrovasculature, particularly in fAD patients. Compared with sAD samples, deposits from fAD patients show less intersubject variability, and little overlap exists between fAD and sAD deposits. Finally, we examined whether E22G (Arctic) or E22Q (Dutch) mutants direct the misfolding of WT A beta, leading to fAD-like plaques in vivo. Intracerebrally injecting mutant A beta 40 fibrils into transgenic mice expressing only WT A beta induced the deposition of plaques with many biochemical hallmarks of fAD. Thus, mutant A beta 40 prions induce a conformation of WT A beta similar to that found in fAD deposits. These findings indicate that diverse AD phenotypes likely arise from one or more initial A beta prion conformations, which kinetically dominate the spread of prions in the brain.

    Download full text (pdf)
    fulltext
  • 32.
    Condello, Carlo
    et al.
    Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.;Univ Calif San Francisco, Weill Inst Neurosci, Depat Neurol, San Francisco, CA 94158 USA..
    Maxwell, Alison M.
    Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA..
    Castillo, Erika
    Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA..
    Aoyagi, Atsushi
    Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.;Daiichi Sankyo Co Ltd, Tokyo 1038426, Japan..
    Graff, Caroline
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Solna, Sweden.;Karolinska Univ Hosp, Unit Hereditary Dementias, SE-17176 Solna, Sweden..
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Univ Hlth Network, Krembil Brain Inst, Toronto, ON M5T 2S8, Canada.;Univ Toronto, Dept Med, Toronto, ON M5S IA8, Canada.;Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON M5S IA8, Canada..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bird, Thomas D.
    Univ Washington, Div Med Genet, Dept Med, Seattle, WA 98195 USA.;Univ Washington, Dept Neurol, Seattle, WA 98195 USA..
    Keene, C. Dirk
    Univ Washington, Dept Lab Med & Pathol, Sch Med, Seattle, WA 98115 USA..
    Seeley, William W.
    Univ Calif San Francisco, Weill Inst Neurosci, Depat Neurol, San Francisco, CA 94158 USA.;Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA..
    Perl, Daniel P.
    Uniformed Serv Univ Hlth Sci, Edward Hebert Sch Med, Dept Pathol Neuropathol, Bethesda, MD 20814 USA..
    Head, Elizabeth
    Univ Calif Irvine, Dept Pathol & Lab Med, Irvine, CA 92697 USA..
    Prusiner, Stanley B.
    Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.;Univ Calif San Francisco, Weill Inst Neurosci, Depat Neurol, San Francisco, CA 94158 USA.;Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA..
    A beta and tau prions feature in the neuropathogenesis of Down syndrome2022In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 119, no 46, article id e2212954119Article in journal (Refereed)
    Abstract [en]

    Down syndrome (DS) is caused by the triplication of chromosome 21 and is the most common chromosomal disorder in humans. Those individuals with DS who live beyond age 40 y develop a progressive dementia that is similar to Alzheimer's disease (AD). Both DS and AD brains exhibit numerous extracellular amyloid plaques composed of A beta and intracellular neurofibrillary tangles composed of tau. Since AD is a double-prion disorder, we asked if both A beta and tau prions feature in DS. Frozen brains from people with DS, familial AD (fAD), sporadic AD (sAD), and age-matched controls were procured from brain biorepositories. We selectively precipitated A beta and tau prions from DS brain homogenates and measured the number of prions using cellular bioassays. In brain extracts from 28 deceased donors with DS, ranging in age from 19 to 65 y, we found nearly all DS brains had readily measurable levels of A beta and tau prions. In a cross-sectional analysis of DS donor age at death, we found that the levels of A beta and tau prions increased with age. In contrast to DS brains, the levels of A beta and tau prions in the brains of 37 fAD and sAD donors decreased as a function of age at death. Whether DS is an ideal model for assessing the efficacy of putative AD therapeutics remains to be determined.

  • 33. Conrad, Chris
    et al.
    Zhu, Jun
    Conrad, Cintia
    Schoenfeld, David
    Fang, Zhide
    Ingelsson, Martin
    Department of Neurology, MassGeneral Institute for Neurodegenerative Disease (MIND), Charlestown, Massachusetts, USA.
    Stamm, Stefan
    Church, George
    Hyman, Bradley T
    Single molecule profiling of tau gene expression in Alzheimer's disease2007In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 103, no 3, p. 1228-1236Article in journal (Refereed)
    Abstract [en]

    Tau is a microtubule-associated protein that is important for establishing and maintaining neuronal morphology. In addition to its role in normal cells, tau protein is involved in many neurodegenerative diseases, e.g. Alzheimer's disease (AD) and frontotemporal dementia, as the main component of intraneuronal aggregates. Alternative splicing of tau gene in the brain can give rise to at least six protein variants. A causative role of skewed tau exon 10 inclusion has been defined in frontotemporal dementia; however, no link was established between the aberrant splicing of tau and AD. Here, we applied a single-molecule-based technology, polymerase colony or polony, to simultaneously monitor tau splicing variant and haplotype profile in sporadic AD and normal brains. We found that the coordinated expression of tau exons 2 and 10 is altered in AD. Additional investigations of cis and trans mechanisms of this observation revealed a decreased protein expression of a known tau splicing factor, htra2-beta-1 in AD, thereby implicating a trans mechanism. Our results demonstrate that dysregulation of combinatorial splicing might serve as a signature for aging-related diseases, and the polony assay could be widely adapted for the study of other tauopathies. Furthermore, splicing-based therapeutics is an emerging area of drug development, and a well-defined and quantitative assay for monitoring single-gene transcriptome will be relevant for such development.

  • 34.
    Danielsson, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Halvardson, Jonatan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Davies, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Moghadam, Behrooz Torabi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Mattisson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rychlicka-Buniowska, Edyta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab. Faculty of Pharmacy and 3P Medicine Laboratory, International Research Agendas Programme, Medical University of Gdańsk, Gdańsk, Poland.
    Jaszczyński, Janusz
    Department of Urology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Kraków Branch, Kraków, Poland.
    Heintz, Julia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Dumanski, Jan P.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Faculty of Pharmacy and 3P Medicine Laboratory, International Research Agendas Programme, Medical University of Gdańsk, Gdańsk, Poland.
    Forsberg, Lars A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Beijer Laboratory of Genome Research, Uppsala, Sweden.
    Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals2020In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 28, no 3, p. 349-357Article in journal (Refereed)
    Abstract [en]

    Mosaic loss of chromosome Y (LOY) is the most common somatic genetic aberration and is associated with increased risk for all-cause mortality, various forms of cancer and Alzheimer's disease, as well as other common human diseases. By tracking LOY frequencies in subjects from which blood samples have been serially collected up to five times during up to 22 years, we observed a pronounced intra-individual variation of changes in the frequency of LOY within individual men over time. We observed that in some individuals the frequency of LOY in blood clearly progressed over time and that in other men, the frequency was constant or showed other types of longitudinal development. The predominant method used for estimating LOY is calculation of the median Log R Ratio of probes located in the male specific part of chromosome Y (mLRRY) from intensity data generated by SNP-arrays, which is difficult to interpret due to its logarithmic and inversed scale. We present here a formula to transform mLRRY-values to percentage of LOY that is a more comprehensible unit. The formula was derived using measurements of LOY from matched samples analysed using SNP-array, whole genome sequencing and a new AMELX/AMELY-based assay for droplet digital PCR. The methods described could be applied for analyses of the vast amount of SNP-array data already generated in the scientific community, allowing further discoveries of LOY associated diseases and outcomes.

    Download full text (pdf)
    fulltext
  • 35.
    de la Vega, Maria Pagnon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Michno, Wojciech
    Univ Gothenburg, Dept Psychiat & Neurochem, S-43180 Gothenburg, Sweden.;UCL, Dept Neurosci, London WC1E 6BT, England..
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Guener, Goekhan
    Tech Univ Munich, German Ctr Neurodegenerat Dis DZNE & Neuroprote, Sch Med, Klinikum Rechts Isar, D-81377 Munich, Germany..
    Zielinski, Mara
    Forschungszentrum Julich, Inst Biol Informat Proc, Julich Ctr Struct Biol, Struct Biochem IBI 7, D-52425 Julich, Germany.;Forschungszentrum Julich, JuStruct, Julich Ctr Struct Biol, D-52425 Julich, Germany..
    Degerman Gunnarsson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Brundin, RoseMarie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Soderberg, Linda
    BioArctic AB, S-11251 Stockholm, Sweden..
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Nilsson, Lars N. G.
    Univ Oslo, Dept Pharmacol, N-0316 Oslo, Norway.;Oslo Univ Hosp, N-0316 Oslo, Norway..
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Willbold, Dieter
    Forschungszentrum Julich, Inst Biol Informat Proc, Julich Ctr Struct Biol, Struct Biochem IBI 7, D-52425 Julich, Germany.;Forschungszentrum Julich, JuStruct, Julich Ctr Struct Biol, D-52425 Julich, Germany.;Heinrich Heine Univ Dusseldorf, Inst Phys Biol, D-40225 Dusseldorf, Germany.;State Univ, Res Ctr Mol Mech Aging & Age Related Dis, Moscow Inst Phys & Technol, Dolgoprudnyi 141701, Russia..
    Mueller, Stephan A.
    Tech Univ Munich, German Ctr Neurodegenerat Dis DZNE & Neuroprote, Sch Med, Klinikum Rechts Isar, D-81377 Munich, Germany..
    Schroeder, Gunnar F.
    Forschungszentrum Julich, Inst Biol Informat Proc, Julich Ctr Struct Biol, Struct Biochem IBI 7, D-52425 Julich, Germany.;Forschungszentrum Julich, JuStruct, Julich Ctr Struct Biol, D-52425 Julich, Germany.;Heinrich Heine Univ Dusseldorf, Phys Dept, D-40225 Dusseldorf, Germany..
    Hanrieder, Jorg
    Univ Gothenburg, Dept Psychiat & Neurochem, S-43180 Gothenburg, Sweden.;UCL, Dept Neurodegenerat Dis, Queen Sq Inst Neurol, London WC1N 3BG, England..
    Lichtenthaler, Stefan F.
    Tech Univ Munich, German Ctr Neurodegenerat Dis DZNE & Neuroprote, Sch Med, Klinikum Rechts Isar, D-81377 Munich, Germany.;Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid beta fibril formation2021In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 13, no 606, article id eabc6184Article in journal (Refereed)
    Abstract [en]

    Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid beta (A beta). Here, we describe the Uppsala APP mutation (Delta 690-695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) A beta 42 and only slightly pathological amyloid-positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing beta-secretase cleavage and affecting alpha-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated A beta, A beta Upp1-42(Delta 19-24), accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.

  • 36. de Rojas, Itziar
    et al.
    Moreno-Grau, Sonia
    Tesi, Niccolo
    Grenier-Boley, Benjamin
    Andrade, Victor
    Jansen, Iris E.
    Pedersen, Nancy L.
    Stringa, Najada
    Zettergren, Anna
    Hernández, Isabel
    Montrreal, Laura
    Antúnez, Carmen
    Antonell, Anna
    Tankard, Rick M.
    Bis, Joshua C.
    Sims, Rebecca
    Bellenguez, Céline
    Quintela, Inés
    González-Perez, Antonio
    Calero, Miguel
    Franco-Macías, Emilio
    Macías, Juan
    Blesa, Rafael
    Cervera-Carles, Laura
    Menéndez-González, Manuel
    Frank-García, Ana
    Royo, Jose Luís
    Moreno, Fermin
    Huerto Vilas, Raquel
    Baquero, Miquel
    Diez-Fairen, Mónica
    Lage, Carmen
    García-Madrona, Sebastián
    García-González, Pablo
    Alarcón-Martín, Emilio
    Valero, Sergi
    Sotolongo-Grau, Oscar
    Ullgren, Abbe
    Naj, Adam C.
    Lemstra, Afina W.
    Benaque, Alba
    Pérez-Cordón, Alba
    Benussi, Alberto
    Rábano, Alberto
    Padovani, Alessandro
    Squassina, Alessio
    de Mendonça, Alexandre
    Arias Pastor, Alfonso
    Kok, Almar A. L.
    Meggy, Alun
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores2021In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 3417Article in journal (Refereed)
    Abstract [en]

    Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.

    Download full text (pdf)
    fulltext
  • 37.
    Degerman Gunnarsson, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    High Tau Levels in Cerebrospinal Fluid Predict Rapid Decline and Increased Dementia Mortality in Alzheimer's Disease2014In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 37, no 3-4, p. 196-206Article in journal (Refereed)
    Abstract [en]

    Objective: Cerebrospinal fluid (CSF) amyloid beta(42) (A beta(42)), total tau (t-tau) and phosphorylated tau (p-tau) are useful as predictors of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia. However, results are contradictory as to whether these biomarkers reflect the future rate of clinical decline. Methods: This is a retrospective study on 196 patients with AD [mild/moderate AD (n = 72) or AD-MCI (n = 124) at baseline] with a follow-up period of 2-9 years' duration (median 6 years). Lumbar punctures were performed at baseline as a part of the diagnostic procedure. Results: We found an increased risk of rapid cognitive decline defined as a drop in the Mini-Mental State Examination score of = 4 points/year in patients with CSF t-tau concentrations above the median (OR 3.31, 95% CI 1.53-7.16) and CSF p-tau above the median (OR 2.53, 95% CI 1.21-5.26). Patients with CSF t-tau in the highest quartile had a higher risk of dying in severe dementia (HR 4.67, 95% CI 1.16-18.82). Conclusions: In this large AD cohort, we found an association between high levels of CSF t-tau and p-tau and a more aggressive course of the disease, measured as a rapid cognitive decline and a higher risk of dying in severe dementia.

  • 38.
    Diamanti, Klev
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Visvanathar, Robin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Pereira, Maria J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Cavalli, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pan, Gang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Kumar, Chanchal
    Translational Science & Experimental Medicine, Early Cardiovascular, Renal and Metabolism, R&D BioPharmaceuticals, AstraZeneca; Karolinska Institute/AstraZeneca Integrated CardioMetabolic Centre (KI/AZ ICMC), Department of Medicine.
    Stanko, Stanko
    Pharmaceutical Technology & Development, AstraZeneca AB; Department of Medicine, Sahlgrenska University Hospital, Gothenburg.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lind, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Integration of whole-body PET/MRI with non-targeted metabolomics provides new insights into insulin sensitivity of various tissuesManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Alteration of various metabolites has been linked to type 2 diabetes (T2D) and insulin resistance. However, identifying significant associations between metabolites and tissue-specific alterations is challenging and requires a multi-omics approach. In this study, we aimed at discovering associations of metabolites from subcutaneous adipose tissue (SAT) and plasma with the volume, the fat fraction (FF) and the insulin sensitivity (Ki) of specific tissues using [18F]FDG PET/MRI.

    Materials and Methods: In a cohort of 42 subjects with different levels of glucose tolerance (normal, prediabetes and T2D) matched for age and body-mass-index (BMI) we calculated associations between parameters of whole-body FDG PET/MRI during clamp and non-targeted metabolomics profiling for SAT and blood plasma. We also used a rule-based classifier to identify a large collection of prevalent patterns of co-dependent metabolites that characterize non-diabetes (ND) and T2D.

    Results: The plasma metabolomics profiling revealed that hepatic fat content was positively associated with tyrosine, and negatively associated with lysoPC(P-16:0). Ki in visceral adipose tissue (VAT) and SAT, was positively associated with several species of lysophospholipids while the opposite applied to branched-chain amino acids (BCAA) and their intermediates. The adipose tissue metabolomics revealed a positive association between non-esterified fatty acids and, VAT and liver Ki. On the contrary, bile acids and carnitines in adipose tissue were inversely associated with VAT Ki. Finally, we presented a transparent machine-learning model that predicted ND or T2D in “unseen” data with an accuracy of 78%.

    Conclusions: Novel associations of several metabolites from SAT and plasma with the FF, volume and insulin senstivity of various tissues throughout the body were discovered using PET/MRI and a new integrative multi-omics approach. A promising computational model that predicted ND and T2D with high certainty, suggested novel non-linear interdependencies of metabolites.

  • 39. Diogenes, Maria Jose
    et al.
    Dias, Raquel B.
    Rombo, Diogo M.
    Miranda, Hugo Vicente
    Maiolino, Francesca
    Guerreiro, Patricia
    Näsström, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Franquelim, Henri G.
    Oliveira, Luis M. A.
    Castanho, Miguel A. R. B.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Quintas, Alexandre
    Sebastiao, Ana M.
    Lopes, Luisa V.
    Outeiro, Tiago Fleming
    Extracellular Alpha-Synuclein Oligomers Modulate Synaptic Transmission and Impair LTP Via NMDA-Receptor Activation2012In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, no 34, p. 11750-11762Article in journal (Refereed)
    Abstract [en]

    Parkinson's disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of alpha-synuclein (a-syn) in various brain regions is the major pathological hallmark. Indeed, the motor symptoms in PD are caused by a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus. Here, we investigated the impact of a-syn aggregation on AMPA and NMDA receptor-mediated rat hippocampal (CA3-CA1) synaptic transmission and long-term potentiation (LTP), the neurophysiological basis for learning and memory. Our data show that prolonged exposure to a-syn oligomers, but not monomers or fibrils, increases basal synaptic transmission through NMDA receptor activation, triggering enhanced contribution of calcium-permeable AMPA receptors. Slices treated with a-syn oligomers were unable to respond with further potentiation to theta-burst stimulation, leading to impaired LTP. Prior delivery of a low-frequency train reinstated the ability to express LTP, implying that exposure to a-syn oligomers drives the increase of glutamatergic synaptic transmission, preventing further potentiation by physiological stimuli. Our novel findings provide mechanistic insight on how a-syn oligomers may trigger neuronal dysfunction and toxicity in PD and other synucleinopathies.

  • 40.
    Domert, Jakob
    et al.
    Linkoping Univ, Dept Clin Pathol, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Sackmann, Christopher
    Linkoping Univ, Dept Clin Pathol, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Severinsson, Emelie
    Linkoping Univ, Dept Clin Pathol, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Agholme, Lotta
    Linkoping Univ, Dept Clin Pathol, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden..
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hallbeck, Martin
    Linkoping Univ, Dept Clin Pathol, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 12, article id e0168700Article in journal (Refereed)
    Abstract [en]

    Parkinson's disease and other alpha-synucleinopathies are progressive neurodegenerative diseases characterized by aggregates of misfolded alpha-synuclein spreading throughout the brain. Recent evidence suggests that the pathological progression is likely due to neuron-to-neuron transfer of these aggregates between neuroanatomically connected areas of the brain. As the impact of this pathological spreading mechanism is currently debated, we aimed to investigate the transfer and subcellular location of alpha-synuclein species in a novel 3D co-culture human cell model based on highly differentiated SH-SY5Y cells. Fluorescently-labeled monomeric, oligomeric and fibrillar species of alpha-synuclein were introduced into a donor cell population and co-cultured with an EGFP-expressing acceptor-cell population of differentiated neuron-like cells. Subsequent transfer and colocalization of the different species were determined with confocal microscopy. We could confirm cell-to-cell transfer of all three alpha-synuclein species investigated. Interestingly the level of transferred oligomers and fibrils and oligomers were significantly higher than monomers, which could affect the probability of seeding and pathology in the recipient cells. Most alpha-synuclein colocalized with the lysosomal/endosomal system, both pre- and postsynaptically, suggesting its importance in the processing and spreading of alpha-synuclein.

    Download full text (pdf)
    fulltext
  • 41.
    Donadio, Vincenzo
    et al.
    IRCCS Ist Sci Neurol Bologna, UOC Clin Neurol, Bologna, Italy.;IRCCS Ist Sci Neurol Bologna, UOC Clin Neurol, Via Altura 3, I-40139 Bologna, Italy..
    Incensi, Alex
    IRCCS Ist Sci Neurol Bologna, UOC Clin Neurol, Bologna, Italy..
    Rizzo, Giovanni
    IRCCS Ist Sci Neurol Bologna, UOC Clin Neurol, Bologna, Italy..
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Devigili, Grazia
    Fdn IRCCS Ist Neurol Carlo Besta, Milan, Italy..
    De Micco, Rosa
    Univ Campania Luigi Vanvitelli, Dipartimento Sci Med & Chirurg Avanzate, Naples, Italy..
    Tessitore, Alessandro
    Univ Campania Luigi Vanvitelli, Dipartimento Sci Med & Chirurg Avanzate, Naples, Italy..
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurology.
    Parisini, Sara
    IRCCS Ist Sci Neurol Bologna, UOC Clin Neurol, Bologna, Italy..
    Nyman, Dag
    Tedeschi, Gioacchino
    Univ Campania Luigi Vanvitelli, Dipartimento Sci Med & Chirurg Avanzate, Naples, Italy..
    Eleopra, Roberto
    Fdn IRCCS Ist Neurol Carlo Besta, Milan, Italy..
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada; Univ Toronto, Dept Med, Toronto, ON, Canada; Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada.
    Liguori, Rocco
    IRCCS Ist Sci Neurol Bologna, UOC Clin Neurol, Bologna, Italy..
    Phosphorylated α-synuclein in skin Schwann cells: a new biomarker for multiple system atrophy2023In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 146, no 3, p. 1065-1074Article in journal (Refereed)
    Abstract [en]

    Multiple system atrophy (MSA) is characterized by accumulation of phosphorylated α-synuclein (p-syn) as glial cytoplasmic inclusions in the brain and a specific biomarker for this disorder is urgently needed. We aimed at investigating if p-syn can also be detected in skin Remak non-myelinating Schwann cells (RSCs) as Schwann cell cytoplasmic inclusions (SCCi) and may represent a reliable clinical biomarker for MSA.

    This cross-sectional diagnostic study evaluated skin p-syn in 96 patients: 46 with probable MSA (29 with parkinsonism type MSA and 17 with cerebellar type MSA), 34 with Parkinson's disease (PD) and 16 with dementia with Lewy bodies (DLB). We also included 50 healthy control subjects. Patients were recruited from five different medical centres. P-syn aggregates in skin sections were stained by immunofluorescence, followed by analyses with confocal microscopy and immuno-electron microscopy. All analyses were performed in a blinded fashion.

    Overall, p-syn aggregates were found in 78% of MSA patients and 100% of patients with PD/DLB, whereas they could not be detected in controls. As for neuronal aggregates 78% of MSA patients were positive for p-syn in somatic neurons, whereas all PD/DLB patients were positive in autonomic neurons. When analysing the presence of p-syn in RSCs, 74% of MSA patients were positive, whereas no such SCCi could be observed in PD/DLB patients. Analyses by immuno-electron microscopy confirmed that SCCi were only found in cases with MSA and thus absent in those with PD/DLB.

    In conclusion, our findings demonstrate that (i) fibrillar p-syn in RSCs is a pathological hallmark of MSA and may be used as a specific and sensitive disease biomarker; (ii) in Lewy body synucleinopathies (PD/DLB) only neurons contain p-syn deposits; and (iii) the cell-specific deposition of p-syn in the skin thus mirrors that of the brain in many aspects and suggests that non-myelinated glial cells are also involved in the MSA pathogenesis.

  • 42. Duits, Flora H
    et al.
    Martinez-Lage, Pablo
    Paquet, Claire
    Engelborghs, Sebastiaan
    Lleó, Alberto
    Hausner, Lucrezia
    Molinuevo, José L
    Stomrud, Erik
    Farotti, Lucia
    Ramakers, Inez H G B
    Tsolaki, Magda
    Skarsgård, Constance
    Åstrand, Ragnar
    Wallin, Anders
    Vyhnalek, Martin
    Holmber-Clausen, Marie
    Forlenza, Orestes V
    Ghezzi, Laura
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hoff, Erik I
    Roks, Gerwin
    de Mendonça, Alexandre
    Papma, Janne M
    Izagirre, Andrea
    Taga, Mariko
    Struyfs, Hanne
    Alcolea, Daniel A
    Frölich, Lutz
    Balasa, Mircea
    Minthon, Lennart
    Twisk, Jos W R
    Persson, Staffan
    Zetterberg, Henrik
    van der Flier, Wiesje M
    Teunissen, Charlotte E
    Scheltens, Philip
    Blennow, Kaj
    Performance and complications of lumbar puncture in memory clinics: Results of the multicenter lumbar puncture feasibility study2016In: Alzheimer's & Dementia: Journal of the Alzheimer's Association, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 12, no 2, p. 154-163Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Lumbar puncture (LP) is increasingly performed in memory clinics. We investigated patient-acceptance of LP, incidence of and risk factors for post-LP complications in memory clinic populations.

    METHODS: We prospectively enrolled 3868 patients (50% women, age 66 ± 11 years, mini mental state examination 25 ± 5) at 23 memory clinics. We used logistic regression analysis using generalized estimated equations to investigate risk factors for post-LP complications, such as typical postlumbar puncture headache (PLPH) and back pain.

    RESULTS: A total of 1065 patients (31%) reported post-LP complaints; 589 patients (17%) reported back pain, 649 (19%) headache, of which 296 (9%) reported typical PLPH. Only few patients needed medical intervention: 11 (0.3%) received a blood patch, 23 (0.7%) were hospitalized. The most important risk factor for PLPH was medical history of headache. An atraumatic needle and age >65 years were preventive. Gender, rest after LP, or volume of cerebrospinal fluid had no effect.

    DISCUSSIONS: The overall risk of complications is relatively low. If risk factors shown in this study are taken into account, LPs can be safely performed in memory clinics.

  • 43. Dumanski, Jan P.
    et al.
    Forsberg, L. A.
    Rasi, C.
    Razzaghian, H. R.
    Pakalapati, G.
    Waite, L.
    Thilbeault, K. Stanton
    Ronowicz, A.
    Wineinger, N. E.
    Tiwari, H. K.
    Boomsma, D.
    Westerman, M. P.
    Harris, J. R.
    Lyle, R.
    Essand, M.
    Eriksson, F.
    Assimes, T. L.
    Iribarren, C.
    Strachan, E.
    O'Hanlon, T. P.
    Rider, L. G.
    Miller, F. W.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Piotrowski, A.
    Pedersen, N. L.
    Absher, D.
    Age-related accumulation of somatic structural changes in the nuclear genome of human blood cells in vivo2012In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 49, no S1, p. S42-S42Article in journal (Other academic)
  • 44.
    Dumanski, Jan P.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Medical University of Gdańsk.
    Halvardson, Jonatan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Davies, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Rychlicka-Buniowska, Edyta
    Mattisson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Torabi Moghadam, Behrooz
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Nagy, Noemi
    Węglarczyk, Kazimierz
    Bukowska-Strakova, Karolina
    Danielsson, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olszewski, Paweł
    Piotrowski, Arkadiusz
    Oerton, Erin
    Ambicka, Aleksandra
    Przewoźnik, Marcin
    Bełch, Łukasz
    Grodzicki, Tomasz
    Chłosta, Piotr L.
    Imreh, Stefan
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Józkowicz, Alicja
    Siedlar, Maciej
    Klich-Rączka, Alicja
    Jaszczyński, Janusz
    Enroth, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Baran, Jarosław
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Perry, John R. B.
    Ryś, Janusz
    Forsberg, Lars A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Immune cells lacking Y chromosome show dysregulation of autosomal gene expression2021In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 78, no 8, p. 4019-4033Article in journal (Refereed)
    Abstract [en]

    Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer’s disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a “genetic wasteland”, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.

    Download full text (pdf)
    fulltext
  • 45.
    Dumanski, Jan P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lambert, Jean-Charles
    Univ Lille, INSERM, CHU Lille, Pasteur Lille,U1167,RID AGE Risk Factors & Mol De, F-59000 Lille, France..
    Rasi, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Davies, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grenier-Boley, Benjamin
    Univ Lille, INSERM, CHU Lille, Pasteur Lille,U1167,RID AGE Risk Factors & Mol De, F-59000 Lille, France..
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Broad Inst MIT, Cambridge, MA 02142 USA.;Harvard Univ, Cambridge, MA 02142 USA..
    Campion, Dominique
    Rouen Univ Hosp, INSERM, CNR MAJ, U1079, F-76031 Rouen, France..
    Dufouil, Carole
    Victor Segalen Univ, INSERM, U708, F-33076 Bordeaux, France..
    Pasquier, Florence
    Univ Lille, CNR MAJ, Inserm 1171, F-59000 Lille, France.;CHU Lille, F-59000 Lille, France..
    Amouyel, Philippe
    Univ Lille, INSERM, CHU Lille, Pasteur Lille,U1167,RID AGE Risk Factors & Mol De, F-59000 Lille, France..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Forsberg, Lars A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease2016In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 98, no 6, p. 1208-1219Article in journal (Refereed)
    Abstract [en]

    Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.

    Download full text (pdf)
    fulltext
  • 46.
    Dumanski, Jan P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rasi, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lönn, Mikael
    Södertörn University, School of Life Sciences, Biology, Huddinge, Sweden.
    Davies, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Magnusson, Patrik K. E.
    Department of Economics, Stockholm School of Economics, Stockholm, Sweden.
    Lindgren, Cecilia M.
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK;Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.
    Morris, Andrew P.
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK;Department of Biostatistics, University of Liverpool, Liverpool, UK.
    Cesarini, David
    Center for Experimental Social Science, New York University, New York, NY 10012, USA.
    Johannesson, Magnus
    Department of Economics, Stockholm School of Economics, Stockholm, Sweden.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Pedersen, Nancy L.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Forsberg, Lars A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mutagenesis: smoking is associated with mosaic loss of chromosome Y2015In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 347, no 6217, p. 81-83Article in journal (Refereed)
    Abstract [en]

    Tobacco smoking is a risk factor for numerous disorders, including cancers affecting organs outside the respiratory tract. Epidemiological data suggest that smoking is a greater risk factor for these cancers in males compared to females. This observation, together with the fact that males have a higher incidence of and mortality from most non-sex-specific cancers, remains unexplained. Loss of chromosome Y (LOY) in blood cells is associated with increased risk of nonhematological tumors. We demonstrate here that smoking is associated with LOY in blood cells in three independent cohorts [TwinGene: odds ratio (OR) = 4.3, 95% CI = 2.8-6.7; ULSAM: OR = 2.4, 95% CI = 1.6-3.6; and PIVUS: OR = 3.5, 95% CI = 1.4-8.4] encompassing a total of 6014 men. The data also suggest that smoking has a transient and dose-dependent mutagenic effect on LOY status. The finding that smoking induces LOY thus links a preventable risk factor with the most common acquired human mutation.

  • 47.
    Ekmark-Lewén, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Aniszewska, Agata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Molisak, Agnieszka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Gumucio, Astrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Lindström, V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Kahle, P. J.
    Hertie Inst Clin Brain Res, Dept Neurodegenerat, Tubingen, Germany.;German Ctr Neurodegenerat Dis, Tubingen, Germany..
    Nordstrom, E.
    BioArct AB, Stockholm, Sweden..
    Moller, C.
    BioArct AB, Stockholm, Sweden..
    Falting, J.
    BioArct AB, Stockholm, Sweden..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics. BioArct AB, Stockholm, Sweden..
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics. Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada.;Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Dept Med, Toronto, ON, Canada.;Univ Toronto, Lab Med & Pathobiol, Toronto, ON, Canada..
    Reduction of brain stem pathology and transient amelioration of early cognitive symptoms in transgenic mice treated with a monoclonal antibody against α-synuclein oligomers/protofibrils2023In: AGING BRAIN, ISSN 2589-9589, Vol. 4, article id 100086Article in journal (Refereed)
    Abstract [en]

    Immunotherapy against alpha-synuclein (alpha-syn) is a promising novel treatment strategy for Parkinson's disease (PD) and related alpha-synucleinopathies. We have previously shown that systemic treatment with the monoclonal oligomer/protofibril-selective antibody mAb47 targeting cytotoxic alpha-syn leads to reduced central nervous system levels of such species as well as an indication of reduced late-stage symptoms in aged (Thy-1)-h[A30P] alpha-syn transgenic mice. Here, we performed an early-onset long-term treatment study with this antibody to evaluate effects on brain pathology and behavioral outcomes in the same mouse model. Compared to the placebo group, the treatment strongly reduced phosphorylated alpha-syn (pS129 alpha-syn) pathology in the upper brain stem. Moreover, a preserved recognition memory and risk assessment behavior could be seen in antibody-treated mice at six months of age, even although these effects were no longer significant at eleven months of age. Importantly, no evidence of inflammatory responses or other potential toxic effects was seen with the treatment. Taken together, this study supports the strategy to target alpha-syn oligomers/protofibrils with monoclonal antibodies to counteract early symptoms and slow down the progression of PD and other alpha-synucleinopathies.

    Download full text (pdf)
    fulltext
  • 48.
    Ekmark-Lewén, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindstrom, Veronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gumucio, Astrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ihse, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Behere, Anish
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kahle, Philipp J.
    Hertie Inst Clin Brain Res, Dept Neurodegenerat, Tubingen, Germany.;German Ctr Neurodegenerat Dis, Tubingen, Germany..
    Nordstrom, Eva
    BioArctic AB, Stockholm, Sweden..
    Eriksson, Maria
    BioArctic AB, Stockholm, Sweden..
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Early fine motor impairment and behavioral dysfunction in (Thy-1)-h[A30P] alpha-synuclein mice2018In: Brain and Behavior, ISSN 2162-3279, E-ISSN 2162-3279, Vol. 8, no 3, article id e00915Article in journal (Refereed)
    Abstract [en]

    Introduction: Intraneuronal inclusions of alpha-synuclein are commonly found in the brain of patients with Parkinson's disease and other a-synucleinopathies. The correlation between alpha-synuclein pathology and symptoms has been studied in various animal models. In (Thy-1)-h[A30P] alpha-synuclein transgenic mice, behavioral and motor abnormalities were reported from 12 and 15 months, respectively. The aim of this study was to investigate whether these mice also display symptoms at earlier time points.

    Methods: We analyzed gait deficits, locomotion, and behavioral profiles in (Thy-1)-h[A30P] alpha-synuclein and control mice at 2, 8, and 11 months of age. In addition, inflammatory markers, levels of alpha-synuclein oligomers, and tyrosine hydroxylase reactivity were studied.

    Results: Already at 2 months of age, transgenic mice displayed fine motor impairments in the challenging beam test that progressively increased up to 11 months of age. At 8 months, transgenic mice showed a decreased general activity with increased risk-taking behavior in the multivariate concentric square field test. Neuropathological analyses of 8- and 11-month-old mice revealed accumulation of oligomeric alpha-synuclein in neuronal cell bodies. In addition, a decreased presence of tyrosine hydroxylase suggests a dysregulation of the dopaminergic system in the transgenic mice, which in turn may explain some of the motor impairments observed in this mouse model.

    Conclusions: Taken together, our results show that the (Thy-1)-h[A30P] alpha-synuclein transgenic mouse model displays early Parkinson's disease-related symptoms with a concomitant downregulation of the dopaminergic system. Thus, this should be an -appropriate model to study early phenotypes of alpha-synucleinopathies.

    Download full text (pdf)
    fulltext
  • 49.
    Eltom, Khalid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Mothes, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Libard, Sylwia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Department of Pathology, Uppsala University Hospital, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics. University Health Network, Krembil Brain Institute, Toronto, Ontario, Canada. Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine and Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Astrocytic accumulation of tau fibrils isolated from Alzheimer’s disease brains induces inflammation, cell-to-cell propagation and neuronal impairment2024In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 12, no 1, article id 34Article in journal (Refereed)
    Abstract [en]

    Accumulating evidence highlights the involvement of astrocytes in Alzheimer’s disease (AD) progression. We have previously demonstrated that human iPSC-derived astrocytes ingest and modify synthetic tau fibrils in a way that enhances their seeding efficiency. However, synthetic tau fibrils differ significantly from in vivo formed fibrils. To mimic the situation in the brain, we here analyzed astrocytes’ processing of human brain-derived tau fibrils and its consequences for cellular physiology. Tau fibrils were extracted from both AD and control brains, aiming to examine any potential differences in astrocyte response depending on the origin of fibrils. Our results show that human astrocytes internalize, but fail to degrade, both AD and control tau fibrils. Instead, pathogenic, seeding capable tau proteoforms are spread to surrounding cells via tunneling nanotubes and exocytosis. Notably, accumulation of AD tau fibrils induces a stronger reactive state in astrocytes, compared to control fibrils, evident by the augmented expression of vimentin and GFAP, as well as by an increased secretion of the pro-inflammatory cytokines IL-8 and MCP-1. Moreover, conditioned media from astrocytes with AD tau fibril deposits induce synapse and metabolic impairment in human iPSC-derived neurons. Taken together, our data suggest that the accumulation of brain-derived AD tau fibrils induces a more robust inflammatory and neurotoxic phenotype in human astrocytes, accentuating the nature of tau fibrils as an important contributing factor to inflammation and neurodegeneration in AD. 

    Download full text (pdf)
    fulltext
  • 50.
    Emami Khoonsari, Payam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Haggmark, Anna
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, Sci Life Lab, Stockholm, Sweden..
    Lönnberg, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mikus, Maria
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, Sci Life Lab, Stockholm, Sweden..
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nilsson, Peter
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, Sci Life Lab, Stockholm, Sweden..
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala Univ, Dept Chem BMC, Analyt Chem, Uppsala, Sweden..
    Analysis of the Cerebrospinal Fluid Proteome in Alzheimer's Disease2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 3, article id e0150672Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease is a neurodegenerative disorder accounting for more than 50% of cases of dementia. Diagnosis of Alzheimer's disease relies on cognitive tests and analysis of amyloid beta, protein tau, and hyperphosphorylated tau in cerebrospinal fluid. Although these markers provide relatively high sensitivity and specificity for early disease detection, they are not suitable for monitor of disease progression. In the present study, we used label-free shotgun mass spectrometry to analyse the cerebrospinal fluid proteome of Alzheimer's disease patients and non-demented controls to identify potential biomarkers for Alzheimer's disease. We processed the data using five programs (DecyderMS, Maxquant, OpenMS, PEAKS, and Sieve) and compared their results by means of reproducibility and peptide identification, including three different normalization methods. After depletion of high abundant proteins we found that Alzheimer's disease patients had lower fraction of low-abundance proteins in cerebrospinal fluid compared to healthy controls (p<0.05). Consequently, global normalization was found to be less accurate compared to using spiked-in chicken ovalbumin for normalization. In addition, we determined that Sieve and OpenMS resulted in the highest reproducibility and PEAKS was the programs with the highest identification performance. Finally, we successfully verified significantly lower levels (p<0.05) of eight proteins (A2GL, APOM, C1QB, C1QC, C1S, FBLN3, PTPRZ, and SEZ6) in Alzheimer's disease compared to controls using an antibody-based detection method. These proteins are involved in different biological roles spanning from cell adhesion and migration, to regulation of the synapse and the immune system.

    Download full text (pdf)
    fulltext
1234 1 - 50 of 172
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf