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  • 1.
    Abu Hamdeh, Sami
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. BioArctic Neuroscience AB, Stockholm, Sweden.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. BioArctic Neuroscience AB, Stockholm, Sweden.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Marklund, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury2018Inngår i: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 28, nr 4, s. 451-462Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 2.
    Almandoz-Gil, Leire
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Lindström, Veronica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Mapping of Surface-Exposed Epitopes of In Vitro and In Vivo Aggregated Species of Alpha-Synuclein2017Inngår i: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 37, nr 7, s. 1217-1226Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 3.
    Almandoz-Gil, Leire
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lindström, Veronica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Mapping of Surface-Exposed Epitopes of In Vitro and In Vivo Aggregated Species of Alpha-Synuclein2017Inngår i: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 37, nr 7, s. 1217-1226Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 4.
    Almandoz-Gil, Leire
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Persson, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lindström, Veronica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Erlandsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    In situ proximity ligation assay reveals co-localization of alpha-synuclein and SNARE proteins in murine primary neurons2018Inngår i: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 9, artikkel-id 180Artikkel i tidsskrift (Fagfellevurdert)
    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

  • 5.
    Almandoz-Gil, Leire
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Welander, Hedvig
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ihse, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Khoonsari, Payam Emami
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Musunuri, Sravani
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Lendel, Christofer
    KTH Royal Inst Technol, Dept Chem, Stockholm, Sweden.
    Sigvardson, Jessica
    BioArctic AB, Stockholm, Sweden.
    Karlsson, Mikael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Corrigendum to “Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways” [Free Rad. Biol. Med. (2017) 421–431]2018Inngår i: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 117, s. 258-258Artikkel i tidsskrift (Fagfellevurdert)
  • 6.
    Almandoz-Gil, Leire
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Welander, Hedvig
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ihse, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Khoonsari, Payam Emami
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Musunuri, Sravani
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Lendel, Christofer
    KTH, Royal Institute of Technology, Sweden.
    Sigvardson, Jessica
    BioArctic AB, Sweden.
    Karlsson, Mikael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways2017Inngår i: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 110, s. 421-431Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 7. Antonios, Gregory
    et al.
    Saiepour, Nasrin
    Bouter, Yvonne
    Richard, Bernhard C
    Paetau, Anders
    Verkkoniemi-Ahola, Auli
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    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 antibody2013Inngår i: Acta neuropathologica communications, ISSN 2051-5960, Vol. 1, nr 1, s. 56-Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    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 brain2019Inngår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 11, nr 490, artikkel-id eaat8462Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Bogdanovic, Nenad
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Almkvist, Ove
    Näslund, Jan
    Axelman, Karin
    Bird, Thomas D
    Nochlin, David
    Schellenberg, Gerard D
    Wahlund, Lars-Olof
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Clinical and Neuropathological Features of the Arctic APP Gene Mutation Causing Early-Onset Alzheimer Disease2008Inngår i: Archives of Neurology, ISSN 0003-9942, E-ISSN 1538-3687, Vol. 65, nr 4, s. 499-505Artikkel i tidsskrift (Fagfellevurdert)
    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.
    Bergström, Joakim
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Näsström, Thomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Wahlberg, Therese
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Karlsson, Mikael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Nikolajeff, Fredrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Effects of lipid peroxidation metabolites on alpha-synuclein aggregation2009Konferansepaper (Fagfellevurdert)
  • 11. Bertram, Lars
    et al.
    Schjeide, Brit-Maren M.
    Hooli, Basavaraj
    Mullin, Kristina
    Hiltunen, Mikko
    Soininen, Hilkka
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Blacker, Deborah
    Tanzi, Rudolph E.
    No association between CALHM1 and Alzheimer's disease risk2008Inngår i: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 135, nr 6, s. 993-994Artikkel i tidsskrift (Fagfellevurdert)
  • 12. Beyer, Anja-Silke
    et al.
    von Einem, Bjoern
    Schwanzar, Daniel
    Keller, Ilona E
    Hellrung, Anke
    Thal, Dietmar R
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    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 protein2010Inngår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, nr 4, s. 732-743Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 13.
    Björkesten, Johan
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Shen, Qiujin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Wik, Lotta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, 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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kamali-Moghaddam, Masood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Stability of Proteins in Dried Blood Spot Biobanks.2017Inngår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 16, nr 7, s. 1286-1296Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 14.
    Blom, Elin S.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Zetterberg, Henrik
    Fukumoto, Hiroaki
    Blennow, Kaj
    Hyman, Bradley T.
    Irizarry, Michael C.
    Wahlund, Lars-Olof
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    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 genotype2009Inngår i: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 27, nr 5, s. 458-464Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 15.
    Blom, Elin S
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Wang, Yijing
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Skoglund, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Hansson, Anita C
    Ubaldi, Massimo
    Lourdusamy, Anbarasu
    Sommer, Wolfgang H
    Mielke, Matthew
    Hyman, Bradley T
    Heilig, Markus
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Nilsson, Lars N G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Increased mRNA Levels of TCF7L2 and MYC of the Wnt Pathway in Tg-ArcSwe Mice and Alzheimer's Disease Brain2010Inngår i: International journal of Alzheimer's disease, ISSN 2090-0252, Vol. 2011, s. 936580-Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 16.
    Cai, Yixiao
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Lendel, Christofer
    Österlund, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Fasta tillståndets fysik.
    Kasrayan, Alex
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Nikolajeff, Fredrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Karlsson, Mikael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Changes in secondary structure of α-synuclein during oligomerization induced by reactive aldehydes.2015Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 464, nr 1, s. 336-341Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 17.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    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 disease2019Inngår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 9, artikkel-id 55Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 18.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    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 disease2018Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 4, s. E782-E791Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 19. 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 disease2007Inngår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 103, nr 3, s. 1228-1236Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 20.
    Degerman Gunnarsson, Malin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Basun, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kilander, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    High Tau Levels in Cerebrospinal Fluid Predict Rapid Decline and Increased Dementia Mortality in Alzheimer's Disease2014Inngår i: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 37, nr 3-4, s. 196-206Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 21.
    Diamanti, Klev
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik.
    Visvanathar, Robin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Cavalli, Marco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pan, Gang
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, 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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Lind, Lars
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Eriksson, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Wadelius, Claes
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Komorowski, Jan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik.
    Integration of whole-body PET/MRI with non-targeted metabolomics provides new insights into insulin sensitivity of various tissuesManuskript (preprint) (Annet vitenskapelig)
    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.

  • 22. Diogenes, Maria Jose
    et al.
    Dias, Raquel B.
    Rombo, Diogo M.
    Miranda, Hugo Vicente
    Maiolino, Francesca
    Guerreiro, Patricia
    Näsström, Thomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Franquelim, Henri G.
    Oliveira, Luis M. A.
    Castanho, Miguel A. R. B.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Quintas, Alexandre
    Sebastiao, Ana M.
    Lopes, Luisa V.
    Outeiro, Tiago Fleming
    Extracellular Alpha-Synuclein Oligomers Modulate Synaptic Transmission and Impair LTP Via NMDA-Receptor Activation2012Inngår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, nr 34, s. 11750-11762Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 23.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    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 Lysosomes2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 12, artikkel-id e0168700Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 24. 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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    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 study2016Inngår i: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 12, nr 2, s. 154-163Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 25. 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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Piotrowski, A.
    Pedersen, N. L.
    Absher, D.
    Age-related accumulation of somatic structural changes in the nuclear genome of human blood cells in vivo2012Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 49, nr S1, s. S42-S42Artikkel i tidsskrift (Annet vitenskapelig)
  • 26.
    Dumanski, Jan P.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, 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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Davies, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, 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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kilander, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Forsberg, Lars A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease2016Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 98, nr 6, s. 1208-1219Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 27.
    Dumanski, Jan P.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rasi, Chiara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lönn, Mikael
    Södertörn University, School of Life Sciences, Biology, Huddinge, Sweden.
    Davies, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Pedersen, Nancy L.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Forsberg, Lars A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mutagenesis: smoking is associated with mosaic loss of chromosome Y2015Inngår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 347, nr 6217, s. 81-83Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 28.
    Ekmark-Lewén, Sara
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lindstrom, Veronica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Gumucio, Astrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ihse, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Behere, Anish
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Early fine motor impairment and behavioral dysfunction in (Thy-1)-h[A30P] alpha-synuclein mice2018Inngår i: Brain and Behavior, ISSN 2162-3279, E-ISSN 2162-3279, Vol. 8, nr 3, artikkel-id e00915Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 29.
    Emami Khoonsari, Payam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Haggmark, Anna
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, Sci Life Lab, Stockholm, Sweden..
    Lönnberg, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Mikus, Maria
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, Sci Life Lab, Stockholm, Sweden..
    Kilander, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Nilsson, Peter
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, Sci Life Lab, Stockholm, Sweden..
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Shevchenko, Ganna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala Univ, Dept Chem BMC, Analyt Chem, Uppsala, Sweden..
    Analysis of the Cerebrospinal Fluid Proteome in Alzheimer's Disease2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 3, artikkel-id e0150672Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 30.
    Emami Khoonsari, Payam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Shevchenko, Ganna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Herman, Stephanie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Remnestal, Julia
    KTH Royal Inst Technol, Dept Prot Sci, Div Affin Prote, SciLifeLab, Stockholm, Sweden.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Brundin, RoseMarie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Degerman Gunnarsson, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kilander, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Zetterberge, Henrik
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Mölndal, Sweden; Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden; UK Dementia Res Inst UCL, London, England; UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London, England.
    Nilsson, Peter
    KTH Royal Inst Technol, Dept Prot Sci, Div Affin Prote, SciLifeLab, Stockholm, Sweden.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers2019Inngår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 67, nr 2, s. 639-651Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Alzheimer’s disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD.

    Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects.

    Methods: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4–9 years and 21 of these converted to AD, whereas 53 remained stable.

    Results: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively.

    Conclusions: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.

  • 31. Escott-Price, Valentina
    et al.
    Bellenguez, Celine
    Wang, Li-San
    Choi, Seung-Hoan
    Harold, Denise
    Jones, Lesley
    Holmans, Peter
    Gerrish, Amy
    Vedernikov, Alexey
    Richards, Alexander
    DeStefano, Anita L.
    Lambert, Jean-Charles
    Ibrahim-Verbaas, Carla A.
    Naj, Adam C.
    Sims, Rebecca
    Jun, Gyungah
    Bis, Joshua C.
    Beecham, Gary W.
    Grenier-Boley, Benjamin
    Russo, Giancarlo
    Thornton-Wells, Tricia A.
    Denning, Nicola
    Smith, Albert V.
    Chouraki, Vincent
    Thomas, Charlene
    Ikram, M. Arfan
    Zelenika, Diana
    Vardarajan, Badri N.
    Kamatani, Yoichiro
    Lin, Chiao-Feng
    Schmidt, Helena
    Kunkle, Brian
    Dunstan, Melanie L.
    Vronskaya, Maria
    Johnson, Andrew D.
    Ruiz, Agustin
    Bihoreau, Marie-Therese
    Reitz, Christiane
    Pasquier, Florence
    Hollingworth, Paul
    Hanon, Olivier
    Fitzpatrick, Annette L.
    Buxbaum, Joseph D.
    Campion, Dominique
    Crane, Paul K.
    Baldwin, Clinton
    Becker, Tim
    Gudnason, Vilmundur
    Cruchaga, Carlos
    Craig, David
    Amin, Najaf
    Berr, Claudine
    Lopez, Oscar L.
    De Jager, Philip L.
    Deramecourt, Vincent
    Johnston, Janet A.
    Evans, Denis
    Lovestone, Simon
    Letenneur, Luc
    Hernandez, Isabel
    Rubinsztein, David C.
    Eiriksdottir, Gudny
    Sleegers, Kristel
    Goate, Alison M.
    Fievet, Nathalie
    Huentelman, Matthew J.
    Gill, Michael
    Brown, Kristelle
    Kamboh, M. Ilyas
    Keller, Lina
    Barberger-Gateau, Pascale
    McGuinness, Bernadette
    Larson, Eric B.
    Myers, Amanda J.
    Dufouil, Carole
    Todd, Stephen
    Wallon, David
    Love, Seth
    Rogaeva, Ekaterina
    Gallacher, John
    St George-Hyslop, Peter
    Clarimon, Jordi
    Lleo, Alberto
    Bayer, Anthony
    Tsuang, Debby W.
    Yu, Lei
    Tsolaki, Magda
    Bossu, Paola
    Spalletta, Gianfranco
    Proitsi, Petra
    Collinge, John
    Sorbi, Sandro
    Garcia, Florentino Sanchez
    Fox, Nick C.
    Hardy, John
    Deniz Naranjo, Maria Candida
    Bosco, Paolo
    Clarke, Robert
    Brayne, Carol
    Galimberti, Daniela
    Scarpini, Elio
    Bonuccelli, Ubaldo
    Mancuso, Michelangelo
    Siciliano, Gabriele
    Moebus, Susanne
    Mecocci, Patrizia
    Del Zompo, Maria
    Maier, Wolfgang
    Hampel, Harald
    Pilotto, Alberto
    Frank-Garcia, Ana
    Panza, Francesco
    Solfrizzi, Vincenzo
    Caffarra, Paolo
    Nacmias, Benedetta
    Perry, William
    Mayhaus, Manuel
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Hakonarson, Hakon
    Pichler, Sabrina
    Carrasquillo, Minerva M.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Beekly, Duane
    Alvarez, Victoria
    Zou, Fanggeng
    Valladares, Otto
    Younkin, Steven G.
    Coto, Eliecer
    Hamilton-Nelson, Kara L.
    Gu, Wei
    Razquin, Cristina
    Pastor, Pau
    Mateo, Ignacio
    Owen, Michael J.
    Faber, Kelley M.
    Jonsson, Palmi V.
    Combarros, Onofre
    O'Donovan, Michael C.
    Cantwell, Laura B.
    Soininen, Hilkka
    Blacker, Deborah
    Mead, Simon
    Mosley, Thomas H., Jr.
    Bennett, David A.
    Harris, Tamara B.
    Fratiglioni, Laura
    Holmes, Clive
    de Bruijn, Renee F. A. G.
    Passmore, Peter
    Montine, Thomas J.
    Bettens, Karolien
    Rotter, Jerome I.
    Brice, Alexis
    Morgan, Kevin
    Foroud, Tatiana M.
    Kukull, Walter A.
    Hannequin, Didier
    Powell, John F.
    Nalls, Michael A.
    Ritchie, Karen
    Lunetta, Kathryn L.
    Kauwe, John S. K.
    Boerwinkle, Eric
    Riemenschneider, Matthias
    Boada, Merce
    Hiltunen, Mikko
    Martin, Eden R.
    Schmidt, Reinhold
    Rujescu, Dan
    Dartigues, Jean-Francois
    Mayeux, Richard
    Tzourio, Christophe
    Hofman, Albert
    Noethen, Markus M.
    Graff, Caroline
    Psaty, Bruce M.
    Haines, Jonathan L.
    Lathrop, Mark
    Pericak-Vance, Margaret A.
    Launer, Lenore J.
    Van Broeckhoven, Christine
    Farrer, Lindsay A.
    van Duijn, Cornelia M.
    Ramirez, Alfredo
    Seshadri, Sudha
    Schellenberg, Gerard D.
    Amouyel, Philippe
    Williams, Julie
    Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 6, s. e94661-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

  • 32.
    Fagerqvist, Therese
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lindström, Veronica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Nordstrom, Eva
    Lord, Anna
    Tucker, Stina M. E.
    Su, Xingjian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sahlin, Charlotte
    Kasrayan, Alex
    Andersson, Jessica
    Welander, Hedvig
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Näsström, Thomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Holmquist, Mats
    Schell, Heinrich
    Kahle, Philipp J.
    Kalimo, Hannu
    Möller, Christer
    Gellerfors, Pär
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Monoclonal antibodies selective for α-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α-synuclein transgenic mice with the disease-causing A30P mutation2013Inngår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 126, nr 1, s. 131-144Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Inclusions of intraneuronal alpha-synuclein (-synuclein) can be detected in brains of patients with Parkinson's disease and dementia with Lewy bodies. The aggregation of -synuclein is a central feature of the disease pathogenesis. Among the different -synuclein species, large oligomers/protofibrils have particular neurotoxic properties and should therefore be suitable as both therapeutic and diagnostic targets. Two monoclonal antibodies, mAb38F and mAb38E2, with high affinity and strong selectivity for large -synuclein oligomers were generated. These antibodies, which do not bind amyloid-beta or tau, recognize Lewy body pathology in brains from patients with Parkinson's disease and dementia with Lewy bodies and detect pathology earlier in -synuclein transgenic mice than linear epitope antibodies. An oligomer-selective sandwich ELISA, based on mAb38F, was set up to analyze brain extracts of the transgenic mice. The overall levels of -synuclein oligomers/protofibrils were found to increase with age in these mice, although the levels displayed a large interindividual variation. Upon subcellular fractionation, higher levels of -synuclein oligomers/protofibrils could be detected in the endoplasmic reticulum around the age when behavioral disturbances develop. In summary, our novel oligomer-selective -synuclein antibodies recognize relevant pathology and should be important tools to further explore the pathogenic mechanisms in Lewy body disorders. Moreover, they could be potential candidates both for immunotherapy and as reagents in an assay to assess a potential disease biomarker.

  • 33.
    Fagerqvist, Therese
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Näsström, Thomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ihse, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lindström, Veronica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sahlin, Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Fangmark Tucker, Stina M
    BioArctic Neuroscience AB.
    Kasaryan, Alex
    BioArctic Neuroscience AB.
    Karlsson, Mikael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Nikolajeff, Fredrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Schell, Heinrich
    Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, Tübingen .
    Outeiro, Tiago. F
    Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisboa. Instituto de Fisiologia, Faculdade de Medicina da Universidade de Lisboa, Lisboa. Department of NeuroDegeneration and Restaurative Research, Universitätsmedizin Göttingen, Göttingen.
    Kahle, Philipp J
    Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, Tübingen .
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Off-pathway alpha-synuclein oligomers seem to alter alpha-synuclein turnover in a cell model but lack seeding capability in vivo2013Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 20, nr 4, s. 233-244Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aggregated α-synuclein is the major component of Lewy bodies, protein inclusions observed in the brain in neurodegenerative disorders such as Parkinson’s disease and dementia with Lewy bodies. Experimental evidence indicates that α-synuclein potentially can be transferred between cells and act as a seed to accelerate the aggregation process. Here, we investigated in vitro and in vivo seeding effects of α-synuclein oligomers induced by the reactive aldehyde 4-oxo-2-nonenal (ONE). As measured by a Thioflavin-T based fibrillization assay, there was an earlier onset of aggregation when α-synuclein oligomers were added to monomeric α-synuclein. In contrast, exogenously added α-synuclein oligomers did not induce aggregation in a cell model. However, cells overexpressing α-synuclein that were treated with the oligomers displayed reduced α-synuclein levels, indicating that internalized oligomers either decreased the expression or accelerated the degradation of transfected α-synuclein. Also in vivo there were no clear seeding effects, as intracerebral injections of α-synuclein oligomers into the neocortex of α-synuclein transgenic mice did not induce formation of Proteinase K resistant α-synuclein pathology. Taken together, we could observe a seeding effect of the ONE-induced α-synuclein oligomers in a fibrillization assay, but neither in a cell nor in a mouse model.

  • 34.
    Feresiadou, Amalia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Landtblom: Neurologi.
    Nilsson, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Press, Rayomand
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden..
    Kmezic, Ivan
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden..
    Nygren, Ingela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Svenningsson, Anders
    Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden..
    Niemelä, Valter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Cunningham, Janet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Burman, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease2019Inngår i: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 332, s. 31-36Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases.

    METHODS: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease.

    RESULTS: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL.

    CONCLUSIONS: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.

  • 35.
    Flygt, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Gumucio, Astrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Uppsala Univ, Dept Publ Hlth & Caring Sci, Geriatr, Uppsala, Sweden..
    Skoglund, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Holm, Jonatan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Marklund, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Human Traumatic Brain Injury Results in Oligodendrocyte Death and Increases the Number of Oligodendrocyte Progenitor Cells2016Inngår i: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 75, nr 6, s. 503-515Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oligodendrocyte (OL) death may contribute to white matter pathology, a common cause of network dysfunction and persistent cognitive problems in patients with traumatic brain injury (TBI). Oligodendrocyte progenitor cells (OPCs) persist throughout the adult CNS and may replace dead OLs. OL death and OPCs were analyzed by immunohistochemistry of human brain tissue samples, surgically removed due to life-threatening contusions and/or focal brain swelling at 60.6 +/- 75 hours (range 4-192 hours) postinjury in 10 severe TBI patients (age 51.7 +/- 18.5 years). Control brain tissue was obtained postmortem from 5 age-matched patients without CNS disorders. TUNEL and CC1 co-labeling was used to analyze apoptotic OLs, which were increased in injured brain tissue (p < 0.05), without correlation with time from injury until surgery. The OPC markers Olig2, A2B5, NG2, and PDGFR-alpha were used. In contrast to the number of single-labeled Olig2, A2B5, NG2, and PDGFR-alpha-positive cells, numbers of Olig2 and A2B5 co-labeled cells were increased in TBI samples (p < 0.05); this was inversely correlated with time from injury to surgery (r = -0.8, p < 0.05). These results indicate that severe focal human TBI results in OL death and increases in OPCs postinjury, which may influence white matter function following TBI.

  • 36.
    Forsberg, Lars A.
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala Univ, Beijer Lab Genome Res, Uppsala, Sweden.
    Halvardson, Jonatan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Rychlicka-Buniowska, Edyta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Danielsson, Marcus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Moghadam, Behrooz Torabi
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Mattisson, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rasi, Chiara
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Davies, Hanna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Lind, Lars
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kilander, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Dumanski, Jan P.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Med Univ Gdansk, Fac Pharm, Gdansk, Poland.
    Mosaic loss of chromosome Y in leukocytes matters2019Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, nr 1, s. 4-7Artikkel i tidsskrift (Annet vitenskapelig)
  • 37.
    Forsberg, Lars A.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Rasi, Chiara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Razzaghian, Hamid R
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Pakalapati, Geeta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Waite, Lindsay
    Thilbeault, Krista Stanton
    Ronowicz, Anna
    Wineinger, Nathan E
    Tiwari, Hemant K
    Boomsma, Dorret
    Westerman, Maxwell P
    Harris, Jennifer R
    Lyle, Robert
    Essand, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Eriksson, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Assimes, Themistocles L
    Iribarren, Carlos
    Strachan, Eric
    O'Hanlon, Terrance P
    Rider, Lisa G
    Miller, Frederick W
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Piotrowski, Arkadiusz
    Pedersen, Nancy L
    Absher, Devin
    Dumanski, Jan P
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Age-related somatic structural changes in the nuclear genome of human blood cells2012Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 90, nr 2, s. 217-228Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we describe age-related accumulation of copy-number variation in the nuclear genomes in vivo and frequency changes for both megabase- and kilobase-range variants. Megabase-range aberrations were found in 3.4% (9 of 264) of subjects ≥60 years old; these subjects included 78 MZ twin pairs and 108 single-born individuals. No such findings were observed in 81 MZ pairs or 180 single-born subjects who were ≤55 years old. Recurrent region- and gene-specific mutations, mostly deletions, were observed. Longitudinal analyses of 43 subjects whose data were collected 7-19 years apart suggest considerable variation in the rate of accumulation of clones carrying structural changes. Furthermore, the longitudinal analysis of individuals with structural aberrations suggests that there is a natural self-removal of aberrant cell clones from peripheral blood. In three healthy subjects, we detected somatic aberrations characteristic of patients with myelodysplastic syndrome. The recurrent rearrangements uncovered here are candidates for common age-related defects in human blood cells. We anticipate that extension of these results will allow determination of the genetic age of different somatic-cell lineages and estimation of possible individual differences between genetic and chronological age. Our work might also help to explain the cause of an age-related reduction in the number of cell clones in the blood; such a reduction is one of the hallmarks of immunosenescence.

  • 38.
    Giedraitis, Vilmantas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Sundelöf, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Irizarry, Michael C
    Gårevik, Nina
    Hyman, Bradley T
    Wahlund, Lars-Olof
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer's disease2007Inngår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 427, nr 3, s. 127-131Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyloid-beta (A beta) with 40 (A beta 40) and 42 (A beta 42) amino acids, the main components of amyloid plaques in the Alzheimer's disease (AD) brain, can be measured in human cerebrospinal fluid (CSF) and plasma. Whereas CSF A beta 42 is decreased in AD, some studies have reported changed plasma A beta levels in AD and in subjects with mild cognitive impairment (MCI). To this date it is unclear if and how CSF and plasma levels of A beta correlate with each other in healthy individuals, albeit earlier studies on AD patients found no correlation between CSF and plasma A beta. We have measured A beta 40 and A beta 42 in paired CSF and plasma samples from patients with AD (n=39), MCI (n=29) and healthy control subjects (n= 18). We observed a clear correlation between CSF and plasma levels for both A beta 40 and A beta 42 in healthy individuals, whereas no such correlation could be seen for AD or MCI cases. Similarly to other studies we also found low levels of A beta 42 in AD CSF, whereas there were no significant differences in plasma A beta levels between the diagnostic groups. Our findings suggest that the normal equilibrium between CSF and plasma A beta may be disrupted with the initiation of amyloid deposition in the brain.

  • 39.
    Gunnarsson, Malin Degerman
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Blennow, Kaj
    Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Neurosci & Physiol, Clin Neurochem Lab, SE-43180 Molndal, Sweden..
    Basun, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kilander, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    High tau levels in cerebrospinal fluid predict nursing home placement and rapid progression in Alzheimer's disease2016Inngår i: Alzheimer's Research & Therapy, E-ISSN 1758-9193, Vol. 8, artikkel-id 22Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Increased concentrations of cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau, as well as decreased amyloid-beta 42 peptide, are biomarkers of Alzheimer's disease (AD) pathology, but few studies have shown an association with AD progression rate. We hypothesized that high CSF tau, as a marker of ongoing neurodegeneration, would predict a more aggressive course of AD, using time to nursing home placement (NHP) as the main outcome. Methods: Our sample inlcuded 234 patients with mild cognitive impairment (MCI) due to AD (n = 134) or mild to moderate AD (n = 100) who underwent lumbar puncture at a memory clinic and were followed for 2-11 years (median 4.9 years). Results: Individuals with CSF t-tau in the highest quartile (>= 900 ng/L) had a higher ratio of NHP, both in the total cohort and in patients with MCI only (adjusted HR 2.17 [95 % CI 1.24-3.80]; HR 2.37 [95 % CI 1.10-5.09], respectively), than the lowest quartile. The association between high t-tau levels and future steep deterioration was confirmed in analyses with conversion to moderate dementia (HR 1.66; 95 % CI 1.08-2.56), rapid decline in Mini Mental State Examination score (>= 4-point drop/12 months), and dying in severe dementia as outcomes. Conclusions: To our knowledge, this is the first study to show that high CSF t-tau levels predict early NHP and conversion to moderate dementia in an AD cohort. Selecting patients with high CSF t-tau, indicating more aggressive neurodegeneration and steeper decline, for AD immunotherapy trials might increase the possibility of showing contrast between active treatment and placebo.

  • 40.
    Gustafsson, Gabriel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Eriksson, Fredrik
    BioArctic Neurosci AB, Stockholm, Sweden..
    Möller, Christer
    BioArctic Neurosci AB, Stockholm, Sweden..
    da Fonseca, Tomas Lopes
    Univ Med Ctr Gottingen, Dept Neurodegenerat & Restorat Res, Gottingen, Germany..
    Outeiro, Tiago F.
    Univ Med Ctr Gottingen, Dept Neurodegenerat & Restorat Res, Gottingen, Germany.;Max Plank Inst Expt Med, Gottingen, Germany..
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Cellular Uptake of alpha-Synuclein Oligomer-Selective Antibodies is Enhanced by the Extracellular Presence of alpha-Synuclein and Mediated via Fc gamma Receptors2017Inngår i: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 37, nr 1, s. 121-131Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Immunotherapy targeting aggregated alpha-synuclein has emerged as a potential treatment strategy against Parkinson's disease and other alpha-synucleinopathies. We have developed alpha-synuclein oligomer/protofibril selective antibodies that reduce toxic alpha-synuclein in a human cell line and, upon intraperitoneal administration, in spinal cord of transgenic mice. Here, we investigated under which conditions and by which mechanisms such antibodies can be internalized by cells. For this purpose, human neuroglioma H4 cells were treated with either monoclonal oligomer/protofibril selective alpha-synuclein antibodies, linear epitope monoclonal alpha-synuclein antibodies, or with a control antibody. The oligomer/protofibril selective antibody mAb47 displayed the highest cellular uptake and was therefore chosen for additional analyses. Next, alpha-synuclein overexpressing cells were incubated with mAb47, which resulted in increased antibody internalization as compared to non-transfected cells. Similarly, regular cells exposed to mAb47 together with media containing alpha-synuclein displayed a higher uptake as compared to cells incubated with regular media. Finally, different Fc gamma receptors were targeted and we then found that blockage of Fc gamma RI and Fc gamma RIIB/C resulted in reduced antibody internalization. Our data thus indicate that the robust uptake of the oligomer/protofibril selective antibody mAb47 by human CNS-derived cells is enhanced by extracellular alpha-synuclein and mediated via Fc gamma receptors. Altogether, our finding lend further support to the belief that alpha-synuclein pathology can be modified by monoclonal antibodies and that these can target toxic alpha-synuclein species in the extracellular milieu. In the context of immunotherapy, antibody binding of alpha-synuclein would then not only block further aggregation but also mediate internalization and subsequent degradation of antigen-antibody complexes.

  • 41.
    Gustafsson, Gabriel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lindström, Veronica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Rostami, Jinar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Nordström, Eva
    BioArct AB, Stockholm.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Erlandsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Alpha-synuclein oligomer-selective antibodies reduce intracellular accumulation and mitochondrial impairment in alpha-synuclein exposed astrocytes2017Inngår i: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 14, artikkel-id 241Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Due to its neurotoxic properties, oligomeric alpha-synuclein (α-syn) has been suggested as an attractive target for passive immunization against Parkinson’s disease (PD). In mouse models of PD, antibody treatment has been shown to lower the levels of pathogenic α-syn species, including oligomers, although the mechanisms of action remain unknown. We have previously shown that astrocytes rapidly engulf α-syn oligomers that are intracellularly stored, rather than degraded, resulting in impaired mitochondria.

    Methods: The aim of the present study was to investigate if the accumulation of α-syn in astrocytes can be affected by α-syn oligomer-selective antibodies. Co-cultures of astrocytes, neurons, and oligodendrocytes were derived from embryonic mouse cortex and exposed to α-syn oligomers or oligomers pre-incubated with oligomer-selective antibodies.

    Results: In the presence of antibodies, the astrocytes displayed an increased clearance of the exogenously added α-syn, and consequently, the α-syn accumulation in the culture was markedly reduced. Moreover, the addition of antibodies rescued the astrocytes from the oligomer-induced mitochondrial impairment.

    Conclusions: Our results demonstrate that oligomer-selective antibodies can prevent α-syn accumulation and mitochondrial dysfunction in cultured astrocytes.

  • 42.
    Gustafsson, Gabriel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lööv, Camilla
    Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA; Harvard Med Sch, Neurosci Program, Boston, MA 02115 USA.
    Persson, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lázaro, Diana F.
    Univ Med Ctr Gottingen, Dept Expt Neurodegenerat, Gottingen, Germany.
    Takeda, Shuko
    Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA; Harvard Med Sch, Neurosci Program, Boston, MA 02115 USA.
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Erlandsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sehlin, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Balaj, Leonora
    Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA; Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA; Harvard Med Sch, Neurosci Program, Boston, MA 02115 USA.
    György, Bence
    Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA; Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA; Harvard Med Sch, Neurosci Program, Boston, MA 02115 USA.
    Hallbeck, Martin
    Linkoping Univ, Dept Clin & Expt Med, Dept Pathol, Linkoping, Sweden.
    Outeiro, Tiago F
    Univ Med Ctr Gottingen, Dept Expt Neurodegenerat, Gottingen, Germany; Max Planck Inst Expt Med, Gottingen, Germany; Newcastle Univ, Med Sch, Inst Neurosci, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
    Breakefield, Xandra O
    Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA; Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA; Harvard Med Sch, Neurosci Program, Boston, MA 02115 USA.
    Hyman, Bradley T
    Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA; Harvard Med Sch, Neurosci Program, Boston, MA 02115 USA.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA; Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA; Harvard Med Sch, Neurosci Program, Boston, MA 02115 USA.
    Secretion and uptake of α-synuclein via extracellular vesicles in cultured cells2018Inngår i: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 38, nr 8, s. 1539-1550Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In Parkinson’s disease and other Lewy body disorders, the propagation of pathology has been accredited to the spreading of extracellular α-synuclein (α-syn). Although the pathogenic mechanisms are not fully understood, cell-to-cell transfer of α-syn via exosomes and other extracellular vesicles (EVs) has been reported. Here, we investigated whether altered molecular properties of α-syn can influence the distribution and secretion of α-syn in human neuroblastoma cells. Different α-syn variants, including α-syn:hemi-Venus and disease-causing mutants, were overexpressed and EVs were isolated from the conditioned medium. Of the secreted α-syn, 0.1–2% was associated with vesicles. The major part of EV α-syn was attached to the outer membrane of vesicles, whereas a smaller fraction was found in their lumen. For α-syn expressed with N-terminal hemi-Venus, the relative levels associated with EVs were higher than for WT α-syn. Moreover, such EV-associated α-syn:hemi-Venus species were internalized in recipient cells to a higher degree than the corresponding free-floating forms. Among the disease-causing mutants, A53T α-syn displayed an increased association with EVs. Taken together, our data suggest that α-syn species with presumably lost physiological functions or altered aggregation properties may shift the cellular processing towards vesicular secretion. Our findings thus lend further support to the tenet that EVs can mediate spreading of harmful α-syn species and thereby contribute to the pathology in α-synucleinopathies.

  • 43.
    Gustafsson, Sofia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lindström, Veronica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Syvänen, Stina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Intact blood-brain barrier transport of small molecular drugs in animal models of amyloid beta and alpha-synuclein pathology2018Inngår i: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 128, s. 482-491Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pathophysiological impairment of the neurovascular unit, including the integrity and dynamics of the blood-brain barrier (BBB), has been denoted both a cause and consequence of neurodegenerative diseases. Pathological impact on BBB drug delivery has also been debated. The aim of the present study was to investigate BBB drug transport, by determining the unbound brain-to-plasma concentration ratio (K-p,K-uu,K-brain), in aged A beta PP-transgenic mice, alpha-synuclein transgenic mice, and wild type mice. Mice were dosed with a cassette of five compounds, including digoxin, levofloxacin (1 mg/kg, s.c.), paliperidone, oxycodone, and diazepam (0.25 mg/kg, s.c.). Brain and blood were collected at 0.5,1, or 3 h after dosage. Drug concentrations were measured using LC-MS/MS. The total brain-to-plasma concentration ratio was calculated and equilibrium dialysis was used to determine the fraction of unbound drug in brain and plasma for all compounds. Together, these three measures were used to determine the Kp,uu,brain value. Despite A beta or alpha-synuclein pathology in the current animal models, no difference was observed in the extent of drug transport across the BBB compared to wild type animals for any of the compounds investigated. Hence, the present study shows that the concept of a leaking barrier within neurodegenerative conditions has to be interpreted with caution when estimating drug transport into the brain. The capability of the highly dynamic BBB to regulate brain drug exposure still seems to be intact despite the presence of pathology. (C) 2017 The Authors. Published by Elsevier Ltd.

  • 44. Guzman, Erika Avendano
    et al.
    Bouter, Yvonne
    Richard, Bernhard C.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Paetau, Anders
    Verkkoniemi-Ahola, Auli
    Wirths, Oliver
    Bayer, Thomas A.
    Abundance of A beta(5-x) x like immunoreactivity in transgenic 5XFAD, APP/PS1KI and 3xTG mice, sporadic and familial Alzheimer's disease2014Inngår i: Molecular Neurodegeneration, ISSN 1750-1326, E-ISSN 1750-1326, Vol. 9, s. 13-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: According to the modified amyloid hypothesis the main event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid beta-peptide (A beta) within neurons. Additionally to full-length peptides, a great diversity of N-truncated A beta variants is derived from the larger amyloid precursor protein (APP). Vast evidence suggests that A beta(x-42) isoforms play an important role triggering neurodegeneration due to its high abundance, amyloidogenic propensity and toxicity. Although N-truncated and A beta(x-42) species have been pointed as crucial players in AD etiology, the A beta(5-x) isoforms have not received much attention. Results: The present study is the first to show immunohistochemical evidence of A beta(5-x) in familial cases of AD (FAD) and its distribution in APP/PS1KI, 5XFAD and 3xTG transgenic mouse models. In order to probe A beta(5-x) peptides we generated the AB5-3 antibody. Positive plaques and congophilic amyloid angiopathy (CAA) were observed among all the FAD cases tested carrying either APP or presenilin 1 (PS1) mutations and most of the sporadic cases of AD (SAD). Different patterns of A beta(5-x) distribution were found in the mouse models carrying different combinations of autosomal mutations in the APP, PS1 and Tau genes. All of them showed extracellular A beta deposits but none CAA. Additionally, they were all affected by a severe amyloid pathology in the hippocampus among other areas. Interestingly, neither 5XFAD nor APP/PS1KI showed any evidence for intraneuronal A beta(5-x). Conclusions: Different degrees of A beta(5-x) accumulations can be found in the transgenic AD mouse models and human cases expressing the sporadic or the familial form of the disease. Due to the lack of intracellular A beta(5-x), these isoforms might not be contributing to early mechanisms in the cascade of events triggering AD pathology. Brain sections obtained from SAD cases showed higher A beta(5-x)-immunoreactivity in vascular deposits than in extracellular plaques, while both are equally important in the FAD cases. The difference may rely on alternative mechanisms involving A beta(5-x) peptides and operating in a divergent way in the late and early onset forms of the disease.

  • 45.
    Gyorgy, Bence
    et al.
    Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA..
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lööv, Camilla
    Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA..
    Takeda, Shuko
    Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA..
    Lannfelt, Lars
    Uppsala Univ, Dept Geriatr, Uppsala, Sweden..
    Hyman, Bradley T.
    Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA..
    Breakefield, Xandra O.
    Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA..
    CRISPR-Cas9 Mediated Gene Editing in a Monogenic Form of Alzheimer's Disease2016Inngår i: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 24, s. S226-S227Artikkel i tidsskrift (Annet vitenskapelig)
  • 46.
    Gyorgy, Bence
    et al.
    Harvard Med Sch, Neurobiol, Boston, MA USA.
    Kleinstiver, Benjamin P.
    Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA USA.
    Garcia, Sara P.
    Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA USA.
    Zaborowski, Mikolaj
    Massachusetts Gen Hosp, Neurol, Boston, MA USA.
    Sousa, Alexander A.
    Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA USA.
    Tsai, Shengdar Q.
    St Jude Childrens Res Hosp, Expt Hematol, Memphis, TN USA.
    Bengtsson, Niclas E.
    Univ Washington, Neurol, Seattle, WA USA.
    Loov, Camilla
    Massachusetts Gen Hosp, MassGen Inst Neurodegenerat, Boston, MA USA.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Chamberlain, Jeffrey S.
    Univ Washington, Neurol, Seattle, WA USA.
    Corey, David P.
    Harvard Med Sch, Neurobiol, Boston, MA USA.
    Aryee, Martin J.
    Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA USA.
    Joung, J. Keith
    Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA USA.
    Breakefield, Xandra O.
    Massachusetts Gen Hosp, Neurol, Boston, MA USA.
    Maguire, Casey A.
    Massachusetts Gen Hosp, Neurol, Boston, MA USA.
    AAV-Vector Integration into CRISPR-Induced Double-Stranded Breaks2018Inngår i: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 26, nr 5, s. 432-433Artikkel i tidsskrift (Annet vitenskapelig)
  • 47.
    Gyorgy, Bence
    et al.
    Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA;Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA;Harvard Med Sch, Ctr NeuroDiscovery, Boston, MA USA;Harvard Med Sch, Dept Neurobiol, 220 Longwood Ave, Boston, MA 02115 USA.
    Loov, Camilla
    Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA;Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA;Harvard Med Sch, Alzheimers Dis Res Ctr, Boston, MA USA.
    Zaborowski, Mikolaj P.
    Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA;Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA;Harvard Med Sch, Ctr NeuroDiscovery, Boston, MA USA;Poznan Univ Med Sci, Div Gynecol Oncol, Dept Gynecol Obstet & Gynecol Oncol, PL-60535 Poznan, Poland.
    Takeda, Shuko
    Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA;Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA;Harvard Med Sch, Alzheimers Dis Res Ctr, Boston, MA USA.
    Kleinstiver, Benjamin P.
    Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA;Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA;Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA USA;Harvard Med Sch, Dept Pathol, Boston, MA USA.
    Commins, Caitlin
    Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA;Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA;Harvard Med Sch, Alzheimers Dis Res Ctr, Boston, MA USA.
    Kastanenka, Ksenia
    Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA;Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA;Harvard Med Sch, Alzheimers Dis Res Ctr, Boston, MA USA.
    Mu, Dakai
    Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA;Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA;Harvard Med Sch, Ctr NeuroDiscovery, Boston, MA USA.
    Volak, Adrienn
    Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA;Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA;Harvard Med Sch, Ctr NeuroDiscovery, Boston, MA USA.
    Giedraitis, Vilmantas
    Uppsala Univ, Dept Publ Hlth & Caring Sci, Rudbeck Lab, Geriatr, Uppsala, Sweden.
    Lannfelt, Lars
    Uppsala Univ, Dept Publ Hlth & Caring Sci, Rudbeck Lab, Geriatr, Uppsala, Sweden.
    Maguire, Casey A.
    Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA;Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA;Harvard Med Sch, Ctr NeuroDiscovery, Boston, MA USA.
    Joung, J. Keith
    Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA;Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA;Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA USA;Harvard Med Sch, Dept Pathol, Boston, MA USA.
    Hyman, Bradley T.
    Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA;Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA;Harvard Med Sch, Alzheimers Dis Res Ctr, Boston, MA USA.
    Breakefield, Xandra O.
    Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA;Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA;Harvard Med Sch, Ctr NeuroDiscovery, Boston, MA USA.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Massachusetts Gen Hosp, Dept Neurol, Boston, USA; Massachusetts Gen Hosp, Dept Radiol, Boston, USA; Harvard Med Sch, Ctr NeuroDiscovery, Boston, MA USA.
    CRISPR/Cas9 Mediated Disruption of the Swedish APP Allele as a Therapeutic Approach for Early-Onset Alzheimer's Disease2018Inngår i: Molecular Therapy - Nucleic Acids, ISSN 2162-2531, E-ISSN 2162-2531, Vol. 11, s. 429-440Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The APPswe (Swedish) mutation in the amyloid precursor protein (APP) gene causes dominantly inherited Alzheimer's disease (AD) as a result of increased beta-secretase cleavage of the amyloid-beta (A beta) precursor protein. This leads to abnormally high A beta levels, not only in brain but also in peripheral tissues of mutation carriers. Here, we selectively disrupted the human mutant APP(sw) allele using CRISPR. By applying CRISPR/Cas9 from Streptococcus pyogenes, we generated allele-specific deletions of either APP(sw) or APP(WT). As measured by ELISA, conditioned media of targeted patient-derived fibroblasts displayed an approximate 60% reduction in secreted A beta. Next, coding sequences for the APP(sw)-specific guide RNA (gRNA) and Cas9 were packaged into separate adeno-associated viral (AAV) vectors. Site-specific indel formation was achieved both in primary neurons isolated from APP(sw) transgenic mouse embryos (Tg2576) and after co-injection of these vectors into hippocampus of adult mice. Taken together, we here present proof-of-concept data that CRISPR/Cas9 can selectively disrupt the APP(sw) allele both ex vivo and in vivo-and thereby decrease pathogenic A beta. Hence, this system may have the potential to be developed as a tool for gene therapy against AD caused by APPswe and other point mutations associated with increased A beta.

  • 48. Hosp, Fabian
    et al.
    Vossfeldt, Hannes
    Heinig, Matthias
    Vasiljevic, Djordje
    Arumughan, Anup
    Wyler, Emanuel
    Landthaler, Markus
    Hubner, Norbert
    Wanker, Erich E.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lalowski, Maciej
    Voigt, Aaron
    Selbach, Matthias
    Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins2015Inngår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 11, nr 7, s. 1134-1146Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several proteins have been linked to neurodegenerative disorders (NDDs), but their molecular function is not completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP) and Presenilin-1 (PSEN1) for Alzheimer's disease (AD), Huntingtin (HTT) for Huntington's disease, Parkin (PARK2) for Parkinson's disease, and Ataxin-1 (ATXN1) for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes in vivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of AD.

  • 49.
    Ingelsson, Martin
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Nilsson, Lars
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Basun, Hans
    Aquilonius, Sten-Magnus
    Institutionen för neurovetenskap. neurologi.
    Lannfelt, Lars
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Konformationsförändrade proteiner orsakar neurodegenerativa sjukdomar2005Inngår i: Läkartidningen, Vol. 102, nr 47, s. 3542-3551Artikkel i tidsskrift (Annet (populærvitenskap, debatt, mm))
  • 50.
    Ingelsson, Martin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ramasamy, Karunya
    Russ, Carsten
    Freeman, Stefanie H
    Orne, Jennifer
    Raju, Susan
    Matsui, Toshifumi
    Growdon, John H
    Frosch, Matthew P
    Ghetti, Bernardino
    Brown, Robert H
    Irizarry, Michael C
    Hyman, Bradley T
    Increase in the relative expression of tau with four microtubule binding repeat regions in frontotemporal lobar degeneration and progressive supranuclear palsy brains2007Inngår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 114, nr 5, s. 471-479Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Some cases of familial frontotemporal dementia (FTD) leading to frontotemporal lobar degeneration (FTLD) are caused by mutations in tau on chromosome 17 (FTDP-17). Certain mutations alter the ratio between four (4R tau) and three (3R tau) repeat tau isoforms whereas cases with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) mainly have 4R tau brain pathology. We assessed tau mRNA and protein levels in frontal cortex from 15 sporadic FTLD, 21 PSP, 5 CBD, 15 Alzheimer’s disease (AD) and 16 control brains. Moreover, we investigated the disease association and possible tau splicing effects of the tau H1 haplotype. Cases with FTLD and PSP had lower tau mRNA levels than control brains. When analyzing 4R tau and 3R tau mRNA separately, control subjects displayed a 4R tau/3R tau ratio of 0.48. Surprisingly, FTLD brains displayed a more elevated ratio (1.32) than PSP brains (1.12). Also, several FTLD and PSP cases had higher 4R tau/3R tau mRNA than FTDP-17 cases, included as reference tissues, and the ratio increase was seen regardless of underlying histopathology, i.e. both for tau-positive and tau-negative FTLD cases. Furthermore, total tau protein levels were slightly decreased in both FTLD and AD as compared to control subjects. Finally, we confirmed the association of tau H1 with PSP, but could not find any haplotype-related effect on tau exon 10 splicing. In conclusion, we demonstrated increased but largely variable 4R tau/3R tau mRNA ratios in FTLD and PSP cases, suggesting heterogeneous pathophysiological processes within these disorders.

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