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Accumulation of amyloid-beta by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
BioArctic Neurosci AB, Warfvinges Vag 35, SE-11251 Stockholm, Sweden..
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2016 (English)In: Molecular Neurodegeneration, ISSN 1750-1326, E-ISSN 1750-1326, Vol. 11, 38Article in journal (Refereed) Published
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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.

Place, publisher, year, edition, pages
2016. Vol. 11, 38
Keyword [en]
Alzheimer's disease, Protofibrils, Glia, Phagocytosis, Degradation, Enlarged vacuole, Microvesicle
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Neurology
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URN: urn:nbn:se:uu:diva-298408DOI: 10.1186/s13024-016-0098-zISI: 000376366500001PubMedID: 27176225OAI: oai:DiVA.org:uu-298408DiVA: diva2:945913
Available from: 2016-07-04 Created: 2016-07-04 Last updated: 2017-11-28Bibliographically approved
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Söllvander, SofiaNikitidou, ElisabethSehlin, DagLannfelt, LarsErlandsson, Anna

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