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  • 1.
    Almandoz-Gil, Leire
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Persson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindström, Veronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    In situ proximity ligation assay reveals co-localization of alpha-synuclein and SNARE proteins in murine primary neurons2018In: Frontiers in Neurology, E-ISSN 1664-2295, Vol. 9, article id 180Article in journal (Refereed)
    Abstract [en]

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

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  • 2.
    Behere, Anish
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Novel visualization of phosphorylated tau and alpha-synuclein aggregates in the Alzheimer’s disease and Parkinson’s disease brainManuscript (preprint) (Other academic)
    Abstract [en]

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

  • 3.
    Beretta, Chiara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Dakhel, Abdulkhalek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Eltom, Khalid
    Rosqvist, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Uzoni, Simon
    Department of Chemistry and Molecular Biology, University of Gothenburg.
    Mothes, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Rostami, Jinar
    Fletcher, John S.
    Department of Chemistry and Molecular Biology, University of Gothenburg.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Michno, Wojciech
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Astrocytes with Alzheimer’s disease pathology provoke lipid droplet mediated cell-to-cell propagation of MHC II complexesManuscript (preprint) (Other academic)
    Abstract [en]

    Background. Astrocytes are critical for maintaining brain homeostasis, but are also highly involved in neuroinflammation. In the Alzheimer disease (AD) brain, reactive, inflammatory astrocytes are situated closely around amyloid β (Aβ) plaques. We have previously shown that reactive astrocytes ingest large quantities of soluble Aβ aggregates, but are unable to degrade the material, which leads to intracellular Aβ accumulation and severe cellular stress. A common response to cellular stress is the formation of lipid droplets (LDs). Novel data indicate that LDs play an important role in inflammatory processes. However, the involvement of LDs in AD inflammation and progression remains unclear.

    Methods. The aim of this study was to investigate how astrocytic Aβ pathology affects lipid metabolism and antigen presentation. For this purpose, human induced pluripotent stem cell (iPSC) derived astrocytes were exposed to soluble Aβ42 aggregates and analyzed over time, using a battery of experimental approaches.

    Results. Our results show that Aβ exposure induces LD accumulation in astrocytes, although the overall lipid composition remains unchanged. Moreover, astrocytes transfer LDs to neighboring cells via tunneling nanotubes (TNTs) and extracellular vesicle (EVs). Interestingly, we found that the antigen presenting protein major histocompatibility complex II (MHCII) is present inside LDs, suggesting an active role of LDs in astrocytic antigen presentation. Immunohistochemical analysis of human brain tissue verified the presence of LD-loaded MHCII+ astrocytes in AD individuals. Moreover, we found infiltrated CD4+ T cells to be in close contact with astrocytes, confirming an astrocyte T cell cross-talk in the AD brain

    Conclusions. Taken together, our data show that Aβ pathology drastically affects lipid storage in astrocytes, which in turn modulates the astrocytic antigen presentation, indicating a role for astrocytic LDs in T cell responses in the AD brain.

  • 4.
    Beretta, Chiara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nikitidou, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gallasch, Linn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Extracellular vesicles from amyloid-beta exposed cell cultures induce severe dysfunction in cortical neurons2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, article id 19656Article in journal (Refereed)
    Abstract [en]

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

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  • 5.
    Beretta, Chiara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Svensson, Elina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics. Department of Neuroinflammation, UCL Queen Square Institute of Neurology, 1 Wakefield Street, WC1N 1PJ London, United Kingdom of Great Britain and Northern Ireland.
    Dakhel, Abdulkhalek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Zyśk, Marlena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Hanrieder, J.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Michno, Wojciech
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Amyloid-β deposits in human astrocytes contain truncated and highly resistant proteoforms2024In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 128, article id 103916Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is a neurodegenerative disorder that develops over decades. Glial cells, including astrocytes are tightly connected to the AD pathogenesis, but their impact on disease progression is still unclear. Our previous data show that astrocytes take up large amounts of aggregated amyloid-beta (Aβ) but are unable to successfully degrade the material, which is instead stored intracellularly. The aim of the present study was to analyze the astrocytic Aβ deposits composition in detail in order to understand their role in AD propagation. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated Aβ42 fibrils and magnetic beads. Live cell imaging and immunocytochemistry confirmed that the ingested Aβ aggregates and beads were transported to the same lysosomal compartments in the perinuclear region, which allowed us to successfully isolate the Aβ deposits from the astrocytes. Using a battery of experimental techniques, including mass spectrometry, western blot, ELISA and electron microscopy we demonstrate that human astrocytes truncate and pack the Aβ aggregates in a way that makes them highly resistant. Moreover, the astrocytes release specifically truncated forms of Aβ via different routes and thereby expose neighboring cells to pathogenic proteins. Taken together, our study establishes a role for astrocytes in mediating Aβ pathology, which could be of relevance for identifying novel treatment targets for AD.

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  • 6.
    Brolin, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Altered distribution of SNARE proteins in primary neurons exposed to different alpha-synuclein speciesManuscript (preprint) (Other academic)
  • 7.
    Brolin, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada.;Univ Toronto, Dept Med, Toronto, ON, Canada.;Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Altered Distribution of SNARE Proteins in Primary Neurons Exposed to Different Alpha-Synuclein Proteoforms2023In: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 43, no 6, p. 3023-3035Article in journal (Refereed)
    Abstract [en]

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

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  • 8.
    Clausen, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Combination of Growth Factor Treatment and Scaffold Deposition Following Experimental Traumatic Brain Injury Show a Temporary Effect on Cellular Regeneration2013In: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 61, p. S196-S196Article in journal (Other academic)
  • 9.
    Clausen, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lindh, Tone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Shabnam, Salimi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Combination of growth factor treatment and scaffold deposition following traumatic brain injury has only a temporary effect on regeneration2014In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1588, p. 37-48Article in journal (Refereed)
    Abstract [en]

    The recovery after traumatic brain injury (TBI) is hampered by the poor regenerative capacity of the brain. Today there is no treatment available that effectively restores lost brain tissue, but much research is focused on the stimulation of endogenous neural stem cells to viably and functionally repopulate the injured parenchyma. It is crucial that the therapies have a proven long-term effect on both regeneration and functional recovery to be clinically interesting. Here we have studied the induction of stem cell activation in rats at three weeks and six weeks after inducing TBI using controlled cortical impact model at a severe setting. We combined intracerebroventricular growth factor and scaffold treatment in order to accomplish an optimal effect on the stem cell regeneration. Immediately after TBI epidermal growth factor infusion with osmotic minipumps was started and continued for seven days. The pumps were removed and an extracellular matrix scaffold containing vascular endothelial growth factor was deposited into the cortical cavity. Three weeks after injury there was a positive effect of the treatment with a significant increase in neuronal and astrocytic regeneration. However, after six weeks there was no difference in the number of newly generated neurons and astrocytes in treated or untreated rats. Evaluation of tissue loss and spatial learning in the Morris water maze corroborated that the treatment had no effect at the later time point. Our results highlight the importance of long-term studies to ensure that a promising effect on tissue regeneration and functional outcome is not only temporary.

  • 10.
    de la Vega, Maria Pagnon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Michno, Wojciech
    Univ Gothenburg, Dept Psychiat & Neurochem, S-43180 Gothenburg, Sweden.;UCL, Dept Neurosci, London WC1E 6BT, England..
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Guener, Goekhan
    Tech Univ Munich, German Ctr Neurodegenerat Dis DZNE & Neuroprote, Sch Med, Klinikum Rechts Isar, D-81377 Munich, Germany..
    Zielinski, Mara
    Forschungszentrum Julich, Inst Biol Informat Proc, Julich Ctr Struct Biol, Struct Biochem IBI 7, D-52425 Julich, Germany.;Forschungszentrum Julich, JuStruct, Julich Ctr Struct Biol, D-52425 Julich, Germany..
    Degerman Gunnarsson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Brundin, RoseMarie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Soderberg, Linda
    BioArctic AB, S-11251 Stockholm, Sweden..
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Nilsson, Lars N. G.
    Univ Oslo, Dept Pharmacol, N-0316 Oslo, Norway.;Oslo Univ Hosp, N-0316 Oslo, Norway..
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Willbold, Dieter
    Forschungszentrum Julich, Inst Biol Informat Proc, Julich Ctr Struct Biol, Struct Biochem IBI 7, D-52425 Julich, Germany.;Forschungszentrum Julich, JuStruct, Julich Ctr Struct Biol, D-52425 Julich, Germany.;Heinrich Heine Univ Dusseldorf, Inst Phys Biol, D-40225 Dusseldorf, Germany.;State Univ, Res Ctr Mol Mech Aging & Age Related Dis, Moscow Inst Phys & Technol, Dolgoprudnyi 141701, Russia..
    Mueller, Stephan A.
    Tech Univ Munich, German Ctr Neurodegenerat Dis DZNE & Neuroprote, Sch Med, Klinikum Rechts Isar, D-81377 Munich, Germany..
    Schroeder, Gunnar F.
    Forschungszentrum Julich, Inst Biol Informat Proc, Julich Ctr Struct Biol, Struct Biochem IBI 7, D-52425 Julich, Germany.;Forschungszentrum Julich, JuStruct, Julich Ctr Struct Biol, D-52425 Julich, Germany.;Heinrich Heine Univ Dusseldorf, Phys Dept, D-40225 Dusseldorf, Germany..
    Hanrieder, Jorg
    Univ Gothenburg, Dept Psychiat & Neurochem, S-43180 Gothenburg, Sweden.;UCL, Dept Neurodegenerat Dis, Queen Sq Inst Neurol, London WC1N 3BG, England..
    Lichtenthaler, Stefan F.
    Tech Univ Munich, German Ctr Neurodegenerat Dis DZNE & Neuroprote, Sch Med, Klinikum Rechts Isar, D-81377 Munich, Germany.;Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid beta fibril formation2021In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 13, no 606, article id eabc6184Article in journal (Refereed)
    Abstract [en]

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

  • 11.
    Ekmark-Lewén, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindstrom, Veronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gumucio, Astrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ihse, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Behere, Anish
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kahle, Philipp J.
    Hertie Inst Clin Brain Res, Dept Neurodegenerat, Tubingen, Germany.;German Ctr Neurodegenerat Dis, Tubingen, Germany..
    Nordstrom, Eva
    BioArctic AB, Stockholm, Sweden..
    Eriksson, Maria
    BioArctic AB, Stockholm, Sweden..
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Early fine motor impairment and behavioral dysfunction in (Thy-1)-h[A30P] alpha-synuclein mice2018In: Brain and Behavior, ISSN 2162-3279, E-ISSN 2162-3279, Vol. 8, no 3, article id e00915Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

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

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  • 13.
    Enarsson, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Larsson, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Extracellular signal-regulated protein kinase signaling is uncoupled from initial differentiation of central nervous system stem cells to neurons2002In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 1, no 2, p. 147-154Article in journal (Refereed)
    Abstract [en]

    Knowledge about signaling pathways in response to external signals is needed to understand the regulation of stem cell proliferation and differentiation toward particular cell fates. The Ras/extracellular signal-regulated kinase (ERK) pathway has been suggested to play an essential role in neuronal differentiation. We have examined ERK signaling in the transition from multipotent stem cell to post-mitotic progeny using primary stem cells from the rat embryonic cortex. Fibroblast growth factor-2 (FGF-2) is a stem cell mitogen, whereas platelet-derived growth factor AA (PDGF-AA) expands a pool of committed neuronal precursors from stem cells. When comparing ERK activation by these growth factors, we found that FGF-2 stimulates high and PDGF-AA lower levels of ERK phosphorylation in stem cells. Differentiation was monitored as down-regulation of the bHLH transcription factor mammalian achaete-scute homologue-1 (MASH1). Even in the absence of active ERK, MASH1 became down-regulated and microtubule-associated protein 2-positive cells could form. Thus, ERK activation seems dispensable for the earliest steps of CNS stem cell differentiation.

  • 14.
    Erlandsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Enarsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Immature neurons from CNS stem cells proliferate in response toplatelet-derived growth factor2001In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 21, no 10, p. 3483-3491Article in journal (Refereed)
    Abstract [en]

    Identifying external signals involved in the regulation of neural stem cell proliferation and differentiation is fundamental to the understanding of CNS development. In this study we show that platelet-derived growth factor (PDGF) can act as a mitogen for neural precursor cells. Multipotent stem cells from developing CNS can be maintained in a proliferative state under serum-free conditions in the presence of fibroblast growth factor-2 (FGF2) and induced to differentiate into neurons, astrocytes, and oligodendrocytes on withdrawal of the mitogen. PDGF has been suggested to play a role during the differentiation into neurons. We have investigated the effect of PDGF on cultured stem cells from embryonic rat cortex. The PDGF alpha-receptor is constantly expressed during differentiation of neural stem cells but is phosphorylated only after PDGF-AA treatment. In contrast, the PDGF beta-receptor is hardly detectable in uncommitted cells, but its expression increases during differentiation. We show that PDGF stimulation leads to c-fos induction, 5'-bromo-2'deoxyuridine incorporation, and an increase in the number of immature cells stained with antibodies to neuronal markers. Our findings suggest that PDGF acts as a mitogen in the early phase of stem cell differentiation to expand the pool of immature neurons.

  • 15.
    Erlandsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Stem cell factor is a chemoattractant and a survival factor for CNS stem cells2004In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 301, no 2, p. 201-210Article in journal (Refereed)
    Abstract [en]

    Migration of neural cells to their final positions is crucial for the correct formation of the central nervous system. Several extrinsic factors are known to be involved in the regulation of neural migration. We asked if stem cell factor (SCF), well known as a chemoattractant and survival factor in the hematopoietic lineage, could elicit similar responses in neural stem cells. For that purpose, a microchemotaxis assay was used to study the effect of SCF on migration of neural stem cells from the embryonic rat cortex. Our results show that SCF-induced chemotaxis and that specific antibodies to SCF or tyrosine kinase inhibitors abolished the migratory response. The SCF-receptor, Kit, was expressed in neural stem cells and in their differentiated progeny. We also show that SCF is a survival factor, but not a mitogen or a differentiation factor for neural stem cells. These data suggest a role for SCF in cell migration and survival in the developing cortex.

  • 16.
    Gustafsson, Gabriel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindström, Veronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Rostami, Jinar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nordström, Eva
    BioArct AB, Stockholm.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Alpha-synuclein oligomer-selective antibodies reduce intracellular accumulation and mitochondrial impairment in alpha-synuclein exposed astrocytes2017In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 14, article id 241Article in journal (Refereed)
    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.

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  • 17.
    Gustafsson, Gabriel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lööv, Camilla
    Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA; Harvard Med Sch, Neurosci Program, Boston, MA 02115 USA.
    Persson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. 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 cells2018In: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 38, no 8, p. 1539-1550Article in journal (Refereed)
    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.

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  • 18. Kenne, Ellinor
    et al.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lindbom, Lennart
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26Article in journal (Other academic)
  • 19. Kenne, Ellinor
    et al.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lindbom, Lennart
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice2012In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 9, p. 17-Article in journal (Refereed)
    Abstract [en]

    Background: Brain edema as a result of secondary injury following traumatic brain injury (TBI) is a major clinical concern. Neutrophils are known to cause increased vascular permeability leading to edema formation in peripheral tissue, but their role in the pathology following TBI remains unclear.

    Methods: In this study we used controlled cortical impact (CCI) as a model for TBI and investigated the role of neutrophils in the response to injury. The outcome of mice that were depleted of neutrophils using an anti-Gr-1 antibody was compared to that in mice with intact neutrophil count. The effect of neutrophil depletion on blood-brain barrier function was assessed by Evan's blue dye extravasation, and analysis of brain water content was used as a measurement of brain edema formation (24 and 48 hours after CCI). Lesion volume was measured 7 and 14 days after CCI. Immunohistochemistry was used to assess cell death, using a marker for cleaved caspase-3 at 24 hours after injury, and microglial/macrophage activation 7 days after CCI. Data were analyzed using Mann-Whitney test for non-parametric data.

    Results: Neutrophil depletion did not significantly affect Evan's blue extravasation at any time-point after CCI. However, neutrophil-depleted mice exhibited a decreased water content both at 24 and 48 hours after CCI indicating reduced edema formation. Furthermore, brain tissue loss was attenuated in neutropenic mice at 7 and 14 days after injury. Additionally, these mice had a significantly reduced number of activated microglia/macrophages 7 days after CCI, and of cleaved caspase-3 positive cells 24 h after injury.

    Conclusion: Our results suggest that neutrophils are involved in the edema formation, but not the extravasation of large proteins, as well as contributing to cell death and tissue loss following TBI in mice.

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  • 20. Khalifa, Shaden A. M.
    et al.
    de Medina, Philippe
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Silvente-Poirot, Sandrine
    Poirot, Marc
    The novel steroidal alkaloids dendrogenin A and B promote proliferation of adult neural stem cells2014In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 446, no 3, p. 681-686Article in journal (Refereed)
    Abstract [en]

    Dendrogenin A (DDA) and dendrogenin B (DDB) are new aminoalkyl oxysterols which display re-differentiation of tumor cells of neuronal origin at nanomolar concentrations. We analyzed the influence of dendrogenins on adult mice neural stem cell proliferation, sphere formation and differentiation. DDA and DDB were found to have potent proliferative effects in neural stem cells. Additionally, they induce neuronal outgrowth from neurospheres during in vitro cultivation. Taken together, our results demonstrate a novel role for dendrogenins A and B in neural stem cell proliferation and differentiation which further increases their likely importance to compensate for neuronal cell loss in the brain. (C) 2014 Elsevier Inc. All rights reserved.

  • 21.
    Konstantinidis, Evangelos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Dakhel, Abdulkhalek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Long-term effects of amyloid-beta accumulation in human iPSC-derived astrocytesManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Alzheimer's disease (AD) is a slowly progressive condition and the most common cause of dementia worldwide. The pathological changes associated with the disease are estimated to occur decades before the first clinical symptoms emerge. Although neurons have been the main research focus, astrocytes have recently gained attention because of their participation in several key cellular functions. Our previous data suggest that astrocytes engulf large amounts of aggregated amyloid-beta (Aβ), but are unable to successfully degrade the material. The intracellular accumulation is, at least initially, very stressful for the astrocytes and long-term Aβ deposits may be detrimental for their functionality. However, if the astrocytes can handle the Aβ storage it could instead be beneficial in a longer perspective, by minimizing the spread of potentially pathogenic Aβ species to neighboring cells.

    Methods: We aimed to evaluate the effects of long-term Aβ inclusions in astrocytes. Mature human induced pluripotent stem cell (hiPSC)-derived astrocytes were exposed to sonicated Aβ42 fibrils and then further cultured for one week or ten weeks in Aβ-free medium. Cells from both time points were analyzed for lysosomal proteins and astrocyte reactivity markers and the medium was screened for inflammatory cytokines. In addition, the overall health of cytoplasmic organelles was investigated by immunocytochemistry and electron microscopy.

    Results: Long-term astrocytes displayed frequent Aβ inclusions that were contained within LAMP1 positive organelles and sustained markers associated with reactivity. Furthermore, increased levels of CCL2/MCP-1 were detected in the media from Aβ-exposed long-term cultures. Finally, Aβ accumulation induced endoplasmic reticulum and mitochondrial swelling as well as formation of pathological lipid structures in astrocytes.

    Conclusions: This study provides valuable information about how intracellular Aβ deposits affect astrocytes over time, and thereby contribute to the understanding of astrocytes role in AD progression.

  • 22.
    Konstantinidis, Evangelos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Dakhel, Abdulkhalek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Long-term effects of amyloid-beta deposits in human iPSC-derived astrocytes2023In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 125, article id 103839Article in journal (Refereed)
    Abstract [en]

    Growing evidence indicates that astrocytes are tightly connected to Alzheimer's disease (AD) pathogenesis. However, the way in which astrocytes participate in AD initiation and progression remains to be clarified. Our previous data show that astrocytes engulf large amounts of aggregated amyloid-beta (A beta) but are unable to successfully degrade the material. In this study, we aimed to evaluate how intracellular A beta-accumulation affects the astrocytes over time. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated A beta-fibrils and then cultured further for one week or ten weeks in A beta-free medium. Cells from both time points were analyzed for lysosomal proteins and astrocyte reactivity markers and the media were screened for inflammatory cytokines. In addition, the overall health of cytoplasmic organelles was investigated by immunocytochemistry and electron microscopy. Our data demonstrate that long-term astrocytes retained frequent A beta-inclusions that were enclosed within LAMP1-positive organelles and sustained markers associated with reactivity. Furthermore, A beta-accumulation resulted in endoplasmic reticulum and mitochondrial swelling, increased secretion of the cytokine CCL2/MCP-1 and formation of pathological lipid structures. Taken together, our results provide valuable information of how intracellular A beta-deposits affect astrocytes, and thereby contribute to the understanding of the role of astrocytes in AD progression.

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  • 23.
    Konstantinidis, Evangelos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Molisak, Agnieszka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Perrin, Florian
    Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Memory Disorders Unit, Charlestown, MA USA..
    Streubel-Gallasch, Linn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Fayad, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kim, Daniel Y.
    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..
    Petri, Karl
    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 02115 USA..
    Aryee, Martin J.
    Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA.;Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA.;Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA.;Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Aguilar, Ximena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    György, Bence
    Inst Mol & Clin Ophthalmol Basel, Basel, Switzerland.;Univ Basel, Dept Ophthalmol, Basel, Switzerland..
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    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 02115 USA..
    Pattanayak, Vikram
    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 02115 USA..
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Berezovska, Oksana
    Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Memory Disorders Unit, Charlestown, MA USA..
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada; Univ Toronto, Dept Med, Toronto, ON, Canada; Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada.
    CRISPR-Cas9 treatment partially restores amyloid-β 42/40 in human fibroblasts with the Alzheimer's disease PSEN1 M146L mutation2022In: Molecular Therapy Nucleic Acids, E-ISSN 2162-2531, Vol. 28, p. 450-461Article in journal (Refereed)
    Abstract [en]

    Presenilin 1 (PS1) is a central component of γ-secretase, an enzymatic complex involved in the generation of the amyloid-β (Aβ) peptide that deposits as plaques in the Alzheimer’s disease (AD) brain. The M146L mutation in the PS1 gene (PSEN1) leads to an autosomal dominant form of early-onset AD by promoting a relative increase in the generation of the more aggregation-prone Aβ42. This change is evident not only in the brain but also in peripheral cells of mutation carriers. In this study we used the CRISPR-Cas9 system from Streptococcus pyogenes to selectively disrupt the PSEN1M146L allele in human fibroblasts. A disruption of more than 50% of mutant alleles was observed in all CRISPR-Cas9-treated samples, resulting in reduced extracellular Aβ42/40 ratios. Fluorescence resonance energy transfer-based conformation and western blot analyses indicated that CRISPR-Cas9 treatment also affects the overall PS1 conformation and reduces PS1 levels. Moreover, our guide RNA did not lead to any detectable editing at the highest-ranking candidate off-target sites identified by ONE-seq and CIRCLE-seq. Overall, our data support the effectiveness of CRISPR-Cas9 in selectively targeting the PSEN1M146L allele and counteracting the AD-associated phenotype. We believe that this system could be developed into a therapeutic strategy for patients with this and other dominant mutations leading to early-onset AD.

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  • 24.
    Konstantinidis, Evangelos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Portal, Benjamin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mothes, Tobias J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindskog, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Amyloid-beta accumulation in astrocytes affects their impact on neuronal function in a human iPSC-based model of Alzheimer’s diseaseManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Although Alzheimer’s disease (AD) is the leading cause of dementia worldwide, there are currently no treatments available that limit the neurodegeneration or slow down the disease progression. Hence, innovative therapeutic approaches are clearly required. The role of astrocytes in AD has recently received much attention, due to their central function in brain homeostasis and synaptic function. Accumulating evidence indicates that astrocytes may lose the ability to fulfil some of their physiological tasks when shifting towards an inflammatory state. Our previous data demonstrate that astrocytes can ingest large amounts of aggregated amyloid-beta (Aβ), but then store, rather than degrade, the ingested material. This incomplete degradation results in severe cellular stress, which could be of relevance for AD progression.

    Methods: In this study, we aimed to investigate how inclusions of aggregated Aβ in astrocytes affect their interplay with neurons, focusing on cellular viability and synaptic function. For this purpose, human induced pluripotent stem cell (hiPSC)-derived astrocytes were exposed to sonicated Αβ42 fibrils and their impact on hiPSC-derived neurons was analyzed by performing neuron-astrocyte co-cultures as well as additions of conditioned media or extracellular vesicles to pure neuronal cultures.

    Results: In the co-culture setup, the presence of Aβ inclusions led to an elevated clearance of dead cells by the astrocytes, indicating increased glial reactivity. In contrast, conditioned media from control, but not from Aβ-exposed astrocytes, benefited the wellbeing of neuronal monocultures. Furthermore, electrophysiological recordings showed a significant decrease in the frequency of excitatory post synaptic current (sEPSCs) in neurons co-cultured with Aβ-astrocytes compared to control astrocytes, while conditioned media from Aβ-exposed astrocytes had the opposite effect.

    Conclusions: Taken together, our results demonstrate that inclusions of aggregated Aβ affect the reactivity state of astrocytes, as well as their ability to support neuronal function.

  • 25.
    Konstantinidis, Evangelos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Portal, Benjamin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Mia Lindskog.
    Mothes, Tobias J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindskog, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Mia Lindskog.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Intracellular deposits of amyloid-beta influence the ability of human iPSC-derived astrocytes to support neuronal function2023In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 20, no 1, article id 3Article in journal (Refereed)
    Abstract [en]

    Background

    Astrocytes are crucial for maintaining brain homeostasis and synaptic function, but are also tightly connected to the pathogenesis of Alzheimer’s disease (AD). Our previous data demonstrate that astrocytes ingest large amounts of aggregated amyloid-beta (Aβ), but then store, rather than degrade the ingested material, which leads to severe cellular stress. However, the involvement of pathological astrocytes in AD-related synaptic dysfunction remains to be elucidated.

    Methods

    In this study, we aimed to investigate how intracellular deposits of Aβ in astrocytes affect their interplay with neurons, focusing on neuronal function and viability. For this purpose, human induced pluripotent stem cell (hiPSC)-derived astrocytes were exposed to sonicated Αβ42 fibrils. The direct and indirect effects of the Αβ-exposed astrocytes on hiPSC-derived neurons were analyzed by performing astrocyte–neuron co-cultures as well as additions of conditioned media or extracellular vesicles to pure neuronal cultures.

    Results

    Electrophysiological recordings revealed significantly decreased frequency of excitatory post-synaptic currents in neurons co-cultured with Aβ-exposed astrocytes, while conditioned media from Aβ-exposed astrocytes had the opposite effect and resulted in hyperactivation of the synapses. Clearly, factors secreted from control, but not from Aβ-exposed astrocytes, benefited the wellbeing of neuronal cultures. Moreover, reactive astrocytes with Aβ deposits led to an elevated clearance of dead cells in the co-cultures.

    Conclusions

    Taken together, our results demonstrate that inclusions of aggregated Aβ affect the reactive state of the astrocytes, as well as their ability to support neuronal function.

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  • 26.
    Lindström, Veronica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gustafsson, Gabriel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sanders, Laurie H
    Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, Dept Neurol, Pittsburgh, PA 15260 USA.
    Howlett, Evan H
    Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, Dept Neurol, Pittsburgh, PA 15260 USA.
    Sigvardson, Jessica
    BioArctic AB, Warfvinges Vag 35, S-11251 Stockholm, Sweden.
    Kasrayan, Alex
    BioArctic AB, Warfvinges Vag 35, S-11251 Stockholm, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage2017In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 82, p. 143-156Article in journal (Refereed)
    Abstract [en]

    The presence of Lewy bodies, mainly consisting of aggregated α-synuclein, is a pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The α-synuclein inclusions are predominantly found in neurons, but also appear frequently in astrocytes. However, the pathological significance of α-synuclein inclusions in astrocytes and the capacity of glial cells to clear toxic α-synuclein species remain unknown. In the present study we investigated uptake, degradation and toxic effects of oligomeric α-synuclein in a co-culture system of primary neurons, astrocytes and oligodendrocytes. Alpha-synuclein oligomers were found to co-localize with the glial cells and the astrocytes were found to internalize particularly large amounts of the protein. Following ingestion, the astrocytes started to degrade the oligomers via the lysosomal pathway but, due to incomplete digestion, large intracellular deposits remained. Moreover, the astrocytes displayed mitochondrial abnormalities. Taken together, our data indicate that astrocytes play an important role in the clearance of toxic α-synuclein species from the extracellular space. However, when their degrading capacity is overburdened, α-synuclein deposits can persist and result in detrimental cellular processes.

  • 27.
    Loov, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Nadadhur, Aishwarya Geeyarpuram
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Wetterhall, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Identification of Injury Specific Proteins in a Cell Culture Model of Traumatic Brain Injury2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 2, p. e55983-Article in journal (Refereed)
    Abstract [en]

    The complicated secondary molecular and cellular mechanisms following traumatic brain injury (TBI) are still not fully understood. In the present study, we have used mass spectrometry to identify injury specific proteins in an in vitro model of TBI. A standardized injury was induced by scalpel cuts through a mixed cell culture of astrocytes, oligodendrocytes and neurons. Twenty-four hours after the injury, cell culture medium and whole-cell fractions were collected for analysis. We found 53 medium proteins and 46 cell fraction proteins that were specifically expressed after injury and the known function of these proteins was elucidated by an extensive literature survey. By using time-lapse microscopy and immunostainings we could link a large proportion of the proteins to specific cellular processes that occur in response to trauma; including cell death, proliferation, lamellipodia formation, axonal regeneration, actin remodeling, migration and inflammation. A high percentage of the proteins uniquely expressed in the medium after injury were actin-related proteins, which normally are situated intracellularly. We show that two of these, ezrin and moesin, are expressed by astrocytes both in the cell culture model and in mouse brain subjected to experimental TBI. Interestingly, we found many inflammation-related proteins, despite the fact that cells were present in the culture. This study contributes with important knowledge about the cellular responses after trauma and identifies several potential cell-specific biomarkers.

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  • 28.
    Lööv, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Molecular Mechanisms in Astrocytic Degradation2013In: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 61, no S1, p. S81-S81Article in journal (Other academic)
  • 29.
    Lööv, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Fernqvist, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Walmsley, Adrian
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Erlansson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Neutralization of LINGO-1 during In Vitro Differentiation of Neural Stem Cells Results in Proliferation of Immature Neurons2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 1, p. e29771-Article in journal (Refereed)
    Abstract [en]

    Identifying external factors that can be used to control neural stem cells division and their differentiation to neurons, astrocytes and oligodendrocytes is of high scientific and clinical interest. Here we show that the Nogo-66 receptor interacting protein LINGO-1 is a potent regulator of neural stem cell maturation to neurons. LINGO-1 is expressed by cortical neural stem cells from E14 mouse embryos and inhibition of LINGO-1 during the first days of neural stem cell differentiation results in decreased neuronal maturation. Compared to neurons in control cultures, which after 6 days of differentiation have long extending neurites, neurons in cultures treated with anti-LINGO-1 antibodies retain an immature, round phenotype with only very short processes. Furthermore, neutralization of LINGO-1 results in a threefold increase in βIII tubulin-positive cells compared to untreated control cultures. By using BrdU incorporation assays we show that the immature neurons in LINGO-1 neutralized cultures are dividing neuroblasts. In contrast to control cultures, in which no cells were double positive for βIII tubulin and BrdU, 36% of the neurons in cultures treated with anti-LINGO-1 antibodies were proliferating after three days of differentiation. TUNEL assays revealed that the amount of cells going through apoptosis during the early phase of differentiation was significantly decreased in cultures treated with anti-LINGO-1 antibodies compared to untreated control cultures. Taken together, our results demonstrate a novel role for LINGO-1 in neural stem cell differentiation to neurons and suggest a possibility to use LINGO-1 inhibitors to compensate for neuronal cell loss in the injured brain.

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  • 30.
    Lööv, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Ebendal, Ted
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Engulfing Astrocytes Protect Neurons from Contact-Induced Apoptosis following Injury2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 3, p. e33090-Article in journal (Refereed)
    Abstract [en]

    Clearing of dead cells is a fundamental process to limit tissue damage following brain injury. Engulfment has classically been believed to be performed by professional phagocytes, but recent data show that non-professional phagocytes are highly involved in the removal of cell corpses in various situations. The role of astrocytes in cell clearance following trauma has however not been studied in detail. We have found that astrocytes actively collect and engulf whole dead cells in an in vitro model of brain injury and thereby protect healthy neurons from bystander cell death. Time-lapse experiments showed that migrating neurons that come in contact with free-floating cell corpses induced apoptosis, while neurons that migrate through groups of dead cells, garnered by astrocytes, remain unaffected. Furthermore, apoptotic cells are present within astrocytes in the mouse brain following traumatic brain injury (TBI), indicating a possible role for astrocytes in engulfment of apoptotic cells in vivo. qRT-PCR analysis showed that members of both ced pathways and Megf8 are expressed in the cell culture, indicating their possible involvement in astrocytic engulfment. Moreover, addition of dead cells had a positive effect on the protein expression of MEGF10, an ortholog to CED1, known to initiate phagocytosis by binding to phosphatidylserine. Although cultured astrocytes have an immense capacity for engulfment, seemingly without adverse effects, the ingested material is stored rather than degraded. This finding might explain the multinuclear astrocytes that are found at the lesion site in patients with various brain disorders.

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  • 31.
    Lööv, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Mitchell, Claire H.
    University of Pennsylvania.
    Simonsson, Martin
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Slow degradation in phagocytic astrocytes can be enhanced by lysosomal acidification2015In: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 63, no 11, p. 1997-2009Article in journal (Refereed)
    Abstract [en]

    Inefficient lysosomal degradation is central in the development of various brain disorders, but the underlying mechanisms and the involvement of different cell types remains elusive. We have previously shown that astrocytes effectively engulf dead cells, but then store, rather than degrade the ingested material. In the present study we identify reasons for the slow digestion and ways to accelerate degradation in primary astrocytes. Our results show that actin-rings surround the phagosomes for long periods of time, which physically inhibit the phago-lysosome fusion. Furthermore, astrocytes express high levels of Rab27a, a protein known to reduce the acidity of lysosomes by Nox2 recruitment, in order to preserve antigens for presentation. We found that Nox2 colocalizes with the ingested material, indicating that it may influence antigen processing also in astrocytes, as they express MHC class II. By inducing long-time acidification of astrocytic lysosomes using acidic nanoparticles, we could increase the digestion of astrocyte-ingested, dead cells. The degradation was, however, normalized over time, indicating that inhibitory pathways are up-regulated in response to the enhanced acidification.

  • 32.
    Lööv, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Nadadhur, Aishwarya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Extracellular Ezrin - a Novel Biomarker for Traumatic Brain Injury2015In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 32, no 4, p. 244-251Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) is a heterogeneous disease, and the discovery of diagnostic and prognostic TBI biomarkers is highly desirable in order to individualize patient care. We have previously published a study in which we identified possible TBI biomarkers by mass spectrometry 24 h after injury in a cell culture model. Ezrin-radixin-moesin (ERM) proteins were found abundantly in the medium after trauma, and in the present study we have identified extracellular ezrin as a possible biomarker for brain trauma by analyzing cell culture medium from injured primary neurons and glia and by measuring ezrin in cerebrospinal fluid (CSF) from both rats and humans. Our results show that extracellular ezrin concentration was substantially increased in cell culture medium after injury, but that the intracellular expression of the protein remained stable over time. Controlled cortical impact injured rats showed an increased amount of ezrin in CSF at both day 3 and day 7 after trauma. Moreover, ezrin was present in all ventricular CSF samples from seven humans with severe TBI. In contrast to intracellular ezrin, which is distinctly activated following TBI, extracellular ezrin is nonphosphorylated. This is the first report of extracellular ERM proteins in human and experimental models of TBI, providing a scientific foundation for further assessment of ezrin as a potential biomarker.

  • 33.
    Lööv, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Wetterhall, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Identification of unique proteins after injury in a cell culture model of TBI2012In: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 26, no 4-5, p. 487-488Article in journal (Other academic)
  • 34.
    Molisak, Agnieszka
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Konstantinidis, Evangelos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Aguilar, Ximena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Stefanis, Leonidas
    Biomedical Research Foundation Academy of Athens, Center of Clinical, Experimental Surgery & Translational Research, Athens, Greece.
    Vekrellis, Kostas
    Biomedical Research Foundation Academy of Athens, Center of Clinical, Experimental Surgery & Translational Research, Athens, Greece.
    Ramachandran, Mohanraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Sarén, Tina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Mary, Bertin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    György, Bence
    University of Basel, Department of Ophthalmology, Basel, Switzerland.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    CRISPR/Cas9 as a tool to disrupt wild-type and A53T SNCA in sporadic and familial Parkinson’s diseaseManuscript (preprint) (Other academic)
    Abstract [en]

    Parkinson’s Disease (PD) is characterized by pathological accumulation of α-synuclein (αSyn) as Lewy bodies and Lewy neurites in the brain. Current treatment strategies can only alleviate the symptoms but do not interfere with the disease progression. With the discovery of the CRISPR/Cas9 gene editing tool, it has become possible to target the generation of pathological protein aggregates at the DNA level. Disrupting the αSyn gene (SNCA) could prevent the formation of Lewy-related pathologies. Here, we have designed two CRISPR/Cas9-based approaches by using guide RNAs (gRNAs) that are targeting either wild-type (WT) SNCA (pan-SNCA) or mutant A53T SNCA that causes early-onset familial PD. We could demonstrate that plasmid vector-mediated transfection of the pan-SNCA gRNA led to robust allelic disruption in HEK293T cells and human fibroblasts and that the editing efficiency was further increased with the use of a lentiviral transduction system. In addition, the SNCA A53T gRNA was specific towards the mutation site, but resulted in low and inconsistent targeting efficiencies in human patient fibroblasts carrying the SNCA A53T mutation. Our results indicate that SNCA can be targeted by CRISPR/Cas9, although the system efficiency varies across different cell types. In the future, systemically administered gene-editing treatments based on CRISPR/Cas9 could provide a valid therapeutic approach for PD patients.

  • 35.
    Mothes, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Portal, Benjamin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Mia Lindskog.
    Konstantinidis, Evangelos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eltom, Khalid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Libard, Sylwia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Streubel-Gallasch, Linn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada; Univ Toronto, Dept Med, Toronto, ON, Canada.
    Rostami, Jinar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindskog, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Mia Lindskog.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Astrocytic uptake of neuronal corpses promotes cell-to-cell spreading of tau pathology2023In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 11, no 1, article id 97Article in journal (Refereed)
    Abstract [en]

    Tau deposits in astrocytes are frequently found in Alzheimer's disease (AD) and other tauopathies. Since astrocytes do not express tau, the inclusions have been suggested to be of neuronal origin. However, the mechanisms behind their appearance and their relevance for disease progression remain unknown. Here we demonstrate, using a battery of experimental techniques that human astrocytes serve as an intermediator, promoting cell-to-cell spreading of pathological tau. Human astrocytes engulf and process, but fail to fully degrade dead neurons with tau pathology, as well as synthetic tau fibrils and tau aggregates isolated from AD brain tissue. Instead, the pathogenic tau is spread to nearby cells via secretion and tunneling nanotube mediated transfer. By performing co-culture experiments we could show that tau-containing astrocytes induce tau pathology in healthy human neurons directly. Furthermore, our results from a FRET based seeding assay, demonstrated that the tau proteoforms secreted by astrocytes have an exceptional seeding capacity, compared to the original tau species engulfed by the cells. Taken together, our study establishes a central role for astrocytes in mediating tau pathology, which could be of relevance for identifying novel treatment targets for AD and other tauopathies.

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  • 36.
    Nikitidou, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Emami Khoonsari, Payam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Increased Release of Apolipoprotein E in Extracellular Vesicles Following Amyloid-β Protofibril Exposure of Neuroglial Co-Cultures2017In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 60, no 1, p. 305-321Article in journal (Refereed)
    Abstract [en]

    Extracellular vesicles (EVs), including exosomes and larger microvesicles, have been implicated to play a role in several conditions, including Alzheimer's disease (AD). Since the EV content mirrors the intracellular environment, it could contribute with important information about ongoing pathological processes and may be a useful source for biomarkers, reflecting the disease progression. The aim of the present study was to analyze the protein content of EVs specifically released from a mixed co-culture of primary astrocytes, neurons, and oligodendrocytes treated with synthetic amyloid-beta (A beta(42)) protofibrils. The EV isolation was performed by ultracentrifugation and validated by transmission electron microscopy. Mass spectrometry analysis of the EV content revealed a total of 807 unique proteins, of which five displayed altered levels in A beta(42) protofibril exposed cultures. The most prominent protein was apolipoprotein E (apoE), and by western blot analysis we could confirm a threefold increase of apoE in EVs from A beta(42) protofibril exposed cells, compared to unexposed cells. Moreover, immunoprecipitation studies demonstrated that apoE was primarily situated inside the EVs, whereas immunocytochemistry indicated that the EVs most likely derived from the astrocytes and the neurons in the culture. The identified A beta-induced sorting of apoE into EVs from cultured neuroglial cells suggests a possible role for intercellular transfer of apoE in AD pathology and encourage future studies to fully elucidate the clinical relevance of this event.

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  • 37.
    Nikitidou, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Rudbeck Lab, Mol Geriatr, Uppsala, Sweden..
    Söllvander, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Rudbeck Lab, Mol Geriatr, Uppsala, Sweden..
    Zyśk, Marlena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. Rudbeck Lab, Mol Geriatr, Uppsala, Sweden..
    Söderberg, L.
    BioArctic Neurosci, Stockholm, Sweden..
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Rudbeck Lab, Mol Geriatr, Uppsala, Sweden..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Rudbeck Lab, Mol Geriatr, Uppsala, Sweden..
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Rudbeck Lab, Mol Geriatr, Uppsala, Sweden..
    The A beta protofibril selective antibody mAb158 prevents accumulation of A beta in astrocytes and rescues neurons from A beta induced apoptosis2017In: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 65, no S1, p. E170-E170Article in journal (Other academic)
  • 38.
    Olsen, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Aguilar, Ximena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Fang, Xiaotian T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer's Disease2018In: Molecular Imaging and Biology, ISSN 1536-1632, E-ISSN 1860-2002, Vol. 20, no 4, p. 605-614Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (A beta) deposition, hyperphosphorylation of tau, and neuroinflammation. Astrocytes, the most abundant glial cell type in the nervous system, respond to neurodegenerative disorders through astrogliosis, i.e., converting to a reactive inflammatory state. The aim of this study was to investigate how in vivo quantification of astrogliosis using positron emission tomography (PET) radioligand deuterium-l-[C-11]deprenyl ([C-11]DED), binding to enzyme monoamine oxidase-B (MAO-B) which is overexpressed in reactive astrocytes during AD, corresponds to expression of glial fibrillary acidic protein (GFAP) and vimentin, i.e., two well-established markers of astrogliosis, during A beta pathology progression. APP(ArcSwe) mice (n = 37) and wild-type (WT) control mice (n = 23), 2-16-month old, were used to investigate biomarkers of astrogliosis. The radioligand, [C-11]DED, was used as an in vivo marker while GFAP, vimentin, and MAO-B were used to investigate astrogliosis and macrophage-associated lectin (Mac-2) to investigate microglia/macrophage activation by immunohistochemistry of the mouse brain. A beta and GFAP levels were also measured with ELISA in brain homogenates. The intrabrain levels of aggregated A beta and reactive astrocytes were found to be elevated in APP(ArcSwe) compared with WT mice. GFAP and vimentin expression increased with age, i.e., with A beta pathology, in the APP(ArcSwe) mice. This was not the case for in vivo marker [C-11]DED that showed elevated binding of the same magnitude in APP(ArcSwe) mice compared with WT mice at both 8 and 16 months. Further, immunohistochemistry indicated that there was limited co-expression of MAO-B and GFAP. MAO-B levels are increased early in A beta pathology progression, while GFAP and vimentin appear to increase later, most likely as a consequence of abundant A beta plaque formation. Thus, [C-11]DED is a useful PET radioligand for the detection of changes in MAO-B at an early stage of AD progression but does not measure the total extent of astrogliosis at advanced stages of A beta pathology.

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  • 39.
    Pagnon de la Vega, María
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Michno, Wojciech
    Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden .
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Güner, Gökhan
    German Center for Neurodegenerative Diseases (DZNE) and Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany .
    Zielinski, Mara
    Institute of Biological Information Processing, Structural Biochemistry (IBI-7) and JuStruct, Jülich Center for Structural Biology, Forschungszentrum Jülich, 52425 Jülich, Germany.
    Löwenmark, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Brundin, RoseMarie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Söderberg, Linda
    BioArctic AB, Stockholm, Sweden.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Lars
    Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Willbold, Dieter
    Institute of Biological Information Processing, Structural Biochemistry (IBI-7) and JuStruct, Jülich Center for Structural Biology, Forschungszentrum Jülich, 52425 Jülich, Germany .
    Müller, Stephan A.
    German Center for Neurodegenerative Diseases (DZNE) and Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany .
    Schöder, Gunnar F.
    Institute of Biological Information Processing, Structural Biochemistry (IBI-7) and JuStruct, Jülich Center for Structural Biology, Forschungszentrum Jülich, 52425 Jülich, Germany .
    Hanrieder, Jörg
    Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden .
    Lichtenthaler, Stefan F.
    German Center for Neurodegenerative Diseases (DZNE) and Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany .
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    The Uppsala APP deletion causes early onset autosomal dominant Alzheimer’s disease by altering APP processing and increasing amyloid-β fibril formationIn: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Science Translational MedicineArticle in journal (Other academic)
  • 40.
    Pagnon de la Vega, María
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical geriatrics.
    Hooley, Monique
    Univ Edinburgh, UK Dementia Res Inst, Edinburgh Med Sch, Edinburgh, Scotland.;Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh, Scotland..
    Konstantinidis, Evangelos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Meier, Silvio R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Rokka, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry. Uppsala Univ Hosp, PET Ctr, Uppsala, Sweden.
    Aguilar, Ximena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Spires-Jones, Tara L.
    Univ Edinburgh, UK Dementia Res Inst, Edinburgh Med Sch, Edinburgh, Scotland.;Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh, Scotland..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics. BioArctic AB, Stockholm, Sweden.
    Nilsson, Lars N. G.
    Oslo Univ Hosp, Dept Pharmacol, Oslo, Norway.;Oslo Univ Hosp, Oslo, Norway..
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Hultqvist, Greta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics. Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada; Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Dept Med & Lab Med, Toronto, ON, Canada; Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Dept Pathobiol, Toronto, ON, Canada.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion2024In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 12, no 1, article id 22Article in journal (Refereed)
    Abstract [en]

    Deposition of amyloid beta (Aβ) into plaques is a major hallmark of Alzheimer’s disease (AD). Different amyloid precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties of Aβ. We recently identified the Uppsala APP mutation (APPUpp), which causes Aβ pathology by a triple mechanism: increased β-secretase and altered α-secretase APP cleavage, leading to increased formation of a unique Aβ conformer that rapidly aggregates and deposits in the brain. The aim of this study was to further explore the effects of APPUpp in a transgenic mouse model (tg-UppSwe), expressing human APP with the APPUpp mutation together with the APPSwe mutation. Aβ pathology was studied in tg-UppSwe brains at different ages, using ELISA and immunohistochemistry. In vivo PET imaging with three different PET radioligands was conducted in aged tg-UppSwe mice and two other mouse models; tg-ArcSwe and tg-Swe. Finally, glial responses to Aβ pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased β-secretase cleavage and suppressed α-secretase cleavage, resulting in AβUpp42 dominated diffuse plaque pathology appearing from the age of 5–6 months. The γ-secretase cleavage was not affected. Contrary to tg-ArcSwe and tg-Swe mice, tg-UppSwe mice were [11C]PiB-PET negative. Antibody-based PET with the 3D6 ligand visualized Aβ pathology in all models, whereas the Aβ protofibril selective mAb158 ligand did not give any signals in tg-UppSwe mice. Moreover, unlike the other two models, tg-UppSwe mice displayed a very faint glial response to the Aβ pathology. The tg-UppSwe mouse model thus recapitulates several pathological features of the Uppsala APP mutation carriers. The presumed unique structural features of AβUpp42 aggregates were found to affect their interaction with anti-Aβ antibodies and profoundly modify the Aβ-mediated glial response, which may be important aspects to consider for further development of AD therapies.

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  • 41.
    Rofo, Fadi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yilmaz, Canan Ugur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Metzendorf, Nicole G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gustavsson, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nilsson, Per
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden..
    Hultqvist, Greta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Enhanced neprilysin-mediated degradation of hippocampal A beta 42 with a somatostatin peptide that enters the brain2021In: Theranostics, E-ISSN 1838-7640, Vol. 11, no 2, p. 789-804Article in journal (Refereed)
    Abstract [en]

    Background: Aggregation of the amyloid-beta (A beta) peptide is one of the main neuropathological events in Alzheimer's disease (AD). Neprilysin is the major enzyme degrading A beta, with its activity enhanced by the neuropeptide somatostatin (SST). SST levels are decreased in the brains of AD patients. The poor delivery of SST over the blood-brain barrier (BBB) and its extremely short half-life of only 3 min limit its therapeutic significance.

    Methods: We recombinantly fused SST to a BBB transporter binding to the transferrin receptor. Using primary neuronal cultures and neuroblastoma cell lines, the ability of the formed fusion protein to activate neprilysin was studied. SST-scFv8D3 was administered to mice overexpressing the A beta-precursor protein (A beta PP) with the Swedish mutation (APPswe) as a single injection or as a course of three injections over a 72 h period. Levels of neprilysin and A beta were quantified using an Enzyme-linked immunosorbent assay (ELISA). Distribution of SST-scFv8D3 in the brain, blood and peripheral organs was studied by radiolabeling with iodine-125.

    Results: The construct, SST-scFv8D3, exhibited 120 times longer half-life than SST alone, reached the brain in high amounts when injected intravenously and significantly increased the brain concentration of neprilysin in APPswe mice. A significant decrease in the levels of membrane-bound A beta 42 was detected in the hippocampus and the adjacent cortical area after only three injections.

    Conclusion: With intravenous injections of our BBB permeable SST peptide, we were able to significantly increase the levels neprilysin, an effect that was followed by a significant and selective degradation of membrane-bound A beta 42 in the hippocampus. Being that membrane-bound A beta triggers neuronal toxicity and the hippocampus is the central brain area in the progression of AD, the study has illuminated a new potential treatment paradigm with a promising safety profile targeting only the disease affected areas.

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  • 42.
    Roshanbin, Sahar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Aniszewska, Agata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gumucio, Astrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Masliah, Eliezer
    NIA, Div Neurosci, NIH, Bethesda, MD 20892 USA..
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ekmark-Lewén, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Age-related increase of alpha-synuclein oligomers is associated with motor disturbances in L61 transgenic mice2021In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 101, p. 207-220Article in journal (Refereed)
    Abstract [en]

    The pathogenesis of Parkinson's disease involves fibrillization and deposition of alpha-synuclein (alpha-syn) into Lewy bodies. Accumulating evidence suggests that alpha-syn oligomers are particularly neurotoxic. Transgenic (tg) mice overexpressing wild-type human alpha-syn under the Thy-1 promoter (L61) reproduce many Parkinson's disease features, but the pathogenetic relevance of alpha-syn oligomers in this mouse model has not been studied in detail. Here, we report an age progressive increase of alpha-syn oligomers in the brain of L61 tg mice. Interestingly, more profound motor symptoms were observed in animals with higher levels of membrane-bound oligomers. As this tg model is X-linked, we also performed subset analyses, indicating that both sexes display a similar age-related increase in alpha-syn oligomers. However, compared with females, males featured increased brain levels of oligomers from an earlier age, in addition to a more severe behavioral phenotype with hyperactivity and thigmotaxis in the open field test. Taken together, our data indicate that alpha-syn oligomers are central to the development of brain pathology and behavioral deficits in the L61 tg alpha-syn mouse model.

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  • 43.
    Rostami, Jinar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Fotaki, Grammatiki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sirois, Julien
    Neuroimmunology Unit, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada.
    Mzezewa, Ropafadzo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Healy, Luke
    Neuroimmunology Unit, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Astrocytes have the capacity to act as antigen-presenting cells in the Parkinson's disease brain2020In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 17, no 1, article id 119Article in journal (Refereed)
    Abstract [en]

    Background

    Many lines of evidence suggest that accumulation of aggregated alpha-synuclein (αSYN) in the Parkinson’s disease (PD) brain causes infiltration of T cells. However, in which ways the stationary brain cells interact with the T cells remain elusive. Here, we identify astrocytes as potential antigen-presenting cells capable of activating T cells in the PD brain. Astrocytes are a major component of the nervous system, and accumulating data indicate that astrocytes can play a central role during PD progression.

    Methods

    To investigate the role of astrocytes in antigen presentation and T-cell activation in the PD brain, we analyzed post mortem brain tissue from PD patients and controls. Moreover, we studied the capacity of cultured human astrocytes and adult human microglia to act as professional antigen-presenting cells following exposure to preformed αSYN fibrils.

    Results

    Our analysis of post mortem brain tissue demonstrated that PD patients express high levels of MHC-II, which correlated with the load of pathological, phosphorylated αSYN. Interestingly, a very high proportion of the MHC-II co-localized with astrocytic markers. Importantly, we found both perivascular and infiltrated CD4+ T cells to be surrounded by MHC-II expressing astrocytes, confirming an astrocyte T cell cross-talk in the PD brain. Moreover, we showed that αSYN accumulation in cultured human astrocytes triggered surface expression of co-stimulatory molecules critical for T-cell activation, while cultured human microglia displayed very poor antigen presentation capacity. Notably, intercellular transfer of αSYN/MHC-II deposits occurred between astrocytes via tunneling nanotubes, indicating spreading of inflammation in addition to toxic protein aggregates.

    Conclusions

    In conclusion, our data from histology and cell culture studies suggest an important role for astrocytes in antigen presentation and T-cell activation in the PD brain, highlighting astrocytes as a promising therapeutic target in the context of chronic inflammation.

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  • 44.
    Rostami, Jinar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Holmqvist, Staffan
    Lund Univ, Wallenberg Neurosci Ctr, Stem Cell Lab CNS Dis Modeling, Dept Expt Med Sci, S-22184 Lund, Sweden.;Lund Univ, Strateg Res Area MultiPk, S-22184 Lund, Sweden.;Lund Univ, Lund Stem Cell Ctr, S-22184 Lund, Sweden..
    Lindström, Veronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sigvardson, Jessica
    BioArctic AB, S-11251 Stockholm, Sweden..
    Westermark, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Roybon, Laurent
    Lund Univ, Wallenberg Neurosci Ctr, Stem Cell Lab CNS Dis Modeling, Dept Expt Med Sci, S-22184 Lund, Sweden.;Lund Univ, Strateg Res Area MultiPk, S-22184 Lund, Sweden.;Lund Univ, Lund Stem Cell Ctr, S-22184 Lund, Sweden..
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes2017In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 37, no 49, p. 11835-11853Article in journal (Refereed)
    Abstract [en]

    Many lines of evidence suggest that the Parkinson's disease (PD)-related protein alpha-synuclein (alpha-SYN) can propagate from cell to cell in a prion-like manner. However, the cellular mechanisms behind the spreading remain elusive. Here, we show that human astrocytes derived from embryonic stem cells actively transfer aggregated alpha-SYN to nearby astrocytes via direct contact and tunneling nanotubes (TNTs). Failure in the astrocytes' lysosomal digestion of excess alpha-SYN oligomers results in alpha-SYN deposits in the trans-Golgi network followed by endoplasmic reticulum swelling and mitochondrial disturbances. The stressed astrocytes respond by conspicuously sending out TNTs, enabling intercellular transfer of alpha-SYN to healthy astrocytes, which in return deliver mitochondria, indicating a TNT-mediated rescue mechanism. Using a pharmacological approach to inhibit TNT formation, we abolished the transfer of both alpha-SYN and mitochondria. Together, our results highlight the role of astrocytes in alpha-SYN cell-to-cell transfer, identifying possible pathophysiological events in the PD brain that could be of therapeutic relevance.

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  • 45.
    Rostami, Jinar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Jäntti, Maria
    Division of Pharmacology and Pharmacotherapy/Drug Research Program, University of Helsinki, University of Helsinki, Finland.
    Cui, Hengjing
    Division of Pharmacology and Pharmacotherapy/Drug Research Program, University of Helsinki, University of Helsinki, Finland.
    Rinne, Maiju K.
    Division of Pharmaceutical Chemistry and Technology/Drug Research Program, Faculty of Pharmacy, University of Helsinki, Finland.
    Kukkonen, Jyrki P.
    Department of Pharmacology, Institute of Biomedicine, Faculty of Medicine, University of Helsinki, Finland.
    Falk, Anna
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Myöhänen, Timo
    Division of Pharmacology and Pharmacotherapy/Drug Research Program, University of Helsinki, Finland; Integrative Physiology and Pharmacology Unit, Institute of Biomedicine, University of Turku, Finland.
    Prolyl oligopeptidase inhibition by KYP-2407 increases alpha-synuclein fibril degradation in neuron-like cells2020In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 131, article id 110788Article in journal (Refereed)
    Abstract [en]

    Growing evidence emphasizes insufficient clearance of pathological alpha-synuclein (αSYN) aggregates in the progression of Parkinson's disease (PD). Consequently, cellular degradation pathways represent a potential therapeutic target. Prolyl oligopeptidase (PREP) is highly expressed in the brain and has been suggested to increase αSYN aggregation and negatively regulate the autophagy pathway. Inhibition of PREP with a small molecule inhibitor, KYP-2407, stimulates autophagy and reduces the oligomeric species of αSYN aggregates in PD mouse models. However, whether PREP inhibition has any effects on intracellular αSYN fibrils has not been studied before. In this study, the effect of KYP2407 on αSYN preformed fibrils (PFFs) was tested in SH-SY5Y cells and human astrocytes. Immunostaining analysis revealed that both cell types accumulated αSYN PFFs intracellularly but KYP-2047 decreased intracellular αSYN deposits only in SH-SY5Y cells, as astrocytes did not show any PREP activity. Western blot analysis confirmed the reduction of high molecular weight αSYN species in SH-SY5Y cell lysates, and secretion of αSYN from SH-SY5Y cells also decreased in the presence of KYP-2407. Accumulation of αSYN inside the SH-SY5Y cells resulted in an increase of the auto-lysosomal proteins p62 and LC3BII, as well as calpain 1 and 2, which have been shown to be associated with PD pathology. Notably, treatment with KYP-2407 significantly reduced p62 and LC3BII levels, indicating an increased autophagic flux, and calpain 1 and 2 levels returned to normal in the presence of KYP-2407. Our findings indicate that PREP inhibition can potentially be used as therapy to reduce the insoluble intracellular αSYN aggregates.

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  • 46.
    Rostami, Jinar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Mothes, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kolahdouzan, Mahshad
    Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University.
    Eriksson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Moslem, Mohsen
    Department of Neuroscience, Karolinska Institutet.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    O'Callaghan, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Healy, Luke M.
    Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University.
    Falk, Anna
    Karolinska institutet.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates2021In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 18, no 1, article id 124Article in journal (Refereed)
    Abstract [en]

    Background

    Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by brain accumulation of aggregated amyloid-beta (Aβ) and alpha-synuclein (αSYN), respectively. In order to develop effective therapies, it is crucial to understand how the Aβ/αSYN aggregates can be cleared. Compelling data indicate that neuroinflammatory cells, including astrocytes and microglia, play a central role in the pathogenesis of AD and PD. However, how the interplay between the two cell types affects their clearing capacity and consequently the disease progression remains unclear.

    Methods

    The aim of the present study was to investigate in which way glial crosstalk influences αSYN and Aβ pathology, focusing on accumulation and degradation. For this purpose, human-induced pluripotent cell (hiPSC)-derived astrocytes and microglia were exposed to sonicated fibrils of αSYN or Aβ and analyzed over time. The capacity of the two cell types to clear extracellular and intracellular protein aggregates when either cultured separately or in co-culture was studied using immunocytochemistry and ELISA. Moreover, the capacity of cells to interact with and process protein aggregates was tracked using time-lapse microscopy and a customized “close-culture” chamber, in which the apical surfaces of astrocyte and microglia monocultures were separated by a <1 mm space.

    Results

    Our data show that intracellular deposits of αSYN and Aβ are significantly reduced in co-cultures of astrocytes and microglia, compared to monocultures of either cell type. Analysis of conditioned medium and imaging data from the “close-culture” chamber experiments indicate that astrocytes secrete a high proportion of their internalized protein aggregates, while microglia do not. Moreover, co-cultured astrocytes and microglia are in constant contact with each other via tunneling nanotubes and other membrane structures. Notably, our live cell imaging data demonstrate that microglia, when attached to the cell membrane of an astrocyte, can attract and clear intracellular protein deposits from the astrocyte.

    Conclusions

    Taken together, our data demonstrate the importance of astrocyte and microglia interactions in Aβ/αSYN clearance, highlighting the relevance of glial cellular crosstalk in the progression of AD- and PD-related brain pathology.

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  • 47.
    Stenler, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roshanbin, Sahar
    Yilmaz Ugur, Canan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rostami, Jinar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Aguilar, Ximena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hultqvist, Greta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Over the BBB and into the cell: Pursuing intracellular targets for immunotherapy of Parkinson’s disease2019Conference paper (Other academic)
    Abstract [en]

    The aim of our research is to modify therapeutic antibodies so that they can reach their dementia target inside cells located on the other side of the blood brain barrier. While the aggregates associated with Alzheimer’s are located extracellularly and thus readily available for antibodies that have crossed the BBB barrier, this is not the case for Parkinson’s disease. In this study, we focus on developing a peptide shuttle that can deliver antibodies not only over the BBB but also into neuronal cells where the Tau and a-synuclein aggregates can be found.

    For this purpose, we have investigated the use of a peptide which binds to a receptor that co- localizes with the aggregates. Our in-house experience suggests that the peptide is not an efficient BBB transporter despite the fact that some groups have used it as such, but that it might be more suitable as a transporter for intracellular delivery.

    We have successfully expressed recombinant antibodies with the peptide on the N-terminal of an antibody targeting the aggregates associated with Parkinson’s disease. Our initial studies indicate that the tyrosine on the N-terminal of the peptide needs to be free and unmodified to be able to enhance uptake into neuronal cells. This hinders the use of the normal labelling method which attaches radiolabelled iodine to tyrosines where the affinity for peptide target would be destroyed. We have been pursuing alternative methods, such as using click chemistry to attach the peptide which will leave the antibody free to be radiolabelled, as well as methods to detect unlabelled antibodies in vivo and in vitro.

    We have assessed the peptide-assisted increase in uptake in appropriate neuronal cell line models. Furthermore, we have studied uptake and retention in brain in mouse models for Parkinson’s disease.

  • 48.
    Streubel-Gallasch, Linn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Giusti, Veronica
    Univ Padua, Dept Biol, Padua, Italy..
    Sandre, Michele
    Univ Padua, Dept Neurosci, Parkinson & Movement Disorders Unit, Padua, Italy.;Univ Padua, PNC, Padua, Italy..
    Tessari, Isabella
    Univ Padua, Dept Biol, Padua, Italy..
    Plotegher, Nicoletta
    Univ Padua, Dept Biol, Padua, Italy..
    Giusto, Elena
    IRCCS San Camillo Hosp, Venice, Italy..
    Masato, Anna
    Univ Padua, Dept Biol, Padua, Italy..
    Iovino, Ludovica
    Univ Padua, Dept Biol, Padua, Italy..
    Battisti, Ilaria
    Univ Padua, Dept Biomed Sci, Padua, Italy..
    Arrigoni, Giorgio
    Univ Padua, Dept Biomed Sci, Padua, Italy.;Univ Padua, CRIBI Biotechnol Ctr, Padua, Italy..
    Shimshek, Derya
    Novartis Inst BioMed Res, Basel, Switzerland..
    Greggio, Elisa
    Univ Padua, Dept Biol, Padua, Italy..
    Tremblay, Marie-Eve
    Univ Victoria, Div Med Sci, Victoria, BC, Canada..
    Bubacco, Luigi
    Univ Padua, Dept Biol, Padua, Italy..
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Civiero, Laura
    Univ Padua, Dept Biol, Padua, Italy.;IRCCS San Camillo Hosp, Venice, Italy..
    Parkinson's Disease-Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance2021In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 58, no 7, p. 3119-3140Article in journal (Refereed)
    Abstract [en]

    Parkinson's disease (PD) is a neurodegenerative, progressive disease without a cure. To prevent PD onset or at least limit neurodegeneration, a better understanding of the underlying cellular and molecular disease mechanisms is crucial. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent one of the most common causes of familial PD. In addition, LRRK2 variants are risk factors for sporadic PD, making LRRK2 an attractive therapeutic target. Mutations in LRRK2 have been linked to impaired alpha-synuclein (alpha-syn) degradation in neurons. However, in which way pathogenic LRRK2 affects alpha-syn clearance by astrocytes, the major glial cell type of the brain, remains unclear. The impact of astrocytes on PD progression has received more attention and recent data indicate that astrocytes play a key role in alpha-syn-mediated pathology. In the present study, we aimed to compare the capacity of wild-type astrocytes and astrocytes carrying the PD-linked G2019S mutation in Lrrk2 to ingest and degrade fibrillary alpha-syn. For this purpose, we used two different astrocyte culture systems that were exposed to sonicated alpha-syn for 24 h and analyzed directly after the alpha-syn pulse or 6 days later. To elucidate the impact of LRRK2 on alpha-syn clearance, we performed various analyses, including complementary imaging, transmission electron microscopy, and proteomic approaches. Our results show that astrocytes carrying the G2019S mutation in Lrrk2 exhibit a decreased capacity to internalize and degrade fibrillar alpha-syn via the endo-lysosomal pathway. In addition, we demonstrate that the reduction of alpha-syn internalization in the Lrrk2 G2019S astrocytes is linked to annexin A2 (AnxA2) loss of function. Together, our findings reveal that astrocytic LRRK2 contributes to the clearance of extracellular alpha-syn aggregates through an AnxA2-dependent mechanism.

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  • 49.
    Streubel-Gallasch, Linn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Zyśk, Marlena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Traumatic brain injury in the presence of Aβ pathology affects neuronal survival, glial activation and autophagy2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 22982Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) presents a widespread health problem in the elderly population. In addition to the acute injury, epidemiological studies have observed an increased probability and earlier onset of dementias in the elderly following TBI. However, the underlying mechanisms of the connection between TBI and Alzheimer’s disease in the aged brain and potential exacerbating factors is still evolving. The aim of this study was to investigate cellular injury-induced processes in the presence of amyloid β (Aβ) pathology. For this purpose, a co-culture system of cortical stem-cell derived astrocytes, neurons and oligodendrocytes were exposed to Aβ42 protofibrils prior to a mechanically induced scratch injury. Cellular responses, including neurodegeneration, glial activation and autophagy was assessed by immunoblotting, immunocytochemistry, ELISA and transmission electron microscopy. Our results demonstrate that the combined burden of Aβ exposure and experimental TBI causes a decline in the number of neurons, the differential expression of the key astrocytic markers glial fibrillary acidic protein and S100 calcium-binding protein beta, mitochondrial alterations and prevents the upregulation of autophagy. Our study provides valuable information about the impact of TBI sustained in the presence of Aβ deposits and helps to advance the understanding of geriatric TBI on the cellular level.

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    FULLTEXT01
  • 50.
    Söllvander, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nikitidou, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Brolin, Robin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Soderberg, Linda
    BioArctic Neurosci AB, Warfvinges Vag 35, SE-11251 Stockholm, Sweden..
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Accumulation of amyloid-beta by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons2016In: Molecular Neurodegeneration, E-ISSN 1750-1326, Vol. 11, article id 38Article in journal (Refereed)
    Abstract [en]

    Background: Despite the clear physical association between activated astrocytes and amyloid-beta (A beta) plaques, the importance of astrocytes and their therapeutic potential in Alzheimer's disease remain elusive. Soluble A beta aggregates, such as protofibrils, have been suggested to be responsible for the widespread neuronal cell death in Alzheimer's disease, but the mechanisms behind this remain unclear. Moreover, ineffective degradation is of great interest when it comes to the development and progression of neurodegeneration. Based on our previous results that astrocytes are extremely slow in degrading phagocytosed material, we hypothesized that astrocytes may be an important player in these processes. Hence, the aim of this study was to clarify the role of astrocytes in clearance, spreading and neuronal toxicity of A beta. Results: To examine the role of astrocytes in A beta pathology, we added A beta protofibrils to a co-culture system of primary neurons and glia. Our data demonstrates that astrocytes rapidly engulf large amounts of A beta protofibrils, but then store, rather than degrade the ingested material. The incomplete digestion results in a high intracellular load of toxic, partly N-terminally truncated A beta and severe lysosomal dysfunction. Moreover, secretion of microvesicles containing N-terminally truncated A beta, induce apoptosis of cortical neurons. Conclusions: Taken together, our results suggest that astrocytes play a central role in the progression of Alzheimer's disease, by accumulating and spreading toxic A beta species.

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