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Accumulation of amyloid-β 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. (Molecular Geriatrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. (Molecular Geriatrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. (Molecular Geriatrics)
BioArctic Neuroscience AB.
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2016 (English)In: Molecular Neurodegeneration, ISSN 1750-1326, E-ISSN 1750-1326Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2016.
Keyword [en]
Alzheimer's Disease, protofibril, glia, phagocytosis, degradation, enlarged vacuole, microvesicle
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-264222OAI: oai:DiVA.org:uu-264222DiVA: diva2:861132
Available from: 2015-10-15 Created: 2015-10-07 Last updated: 2017-12-01
In thesis
1. Amyloid-β Protofibrils in Alzheimer´s Disease: Focus on Antibodies, Inflammation and Astrocytes
Open this publication in new window or tab >>Amyloid-β Protofibrils in Alzheimer´s Disease: Focus on Antibodies, Inflammation and Astrocytes
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Soluble amyloid-beta (Aβ) aggregates, including Aβ protofibrils, play a central role in Alzheimer’s disease (AD) and constitute a potential diagnostic biomarker and a therapeutic target. Aβ protofibrils promote synapse dysfunction and neurodegeneration, but the mechanisms behind these effects remain unclear. The aim of this thesis was to increase the knowledge of Aβ protofibrils in AD pathology.

When measuring low abundant antigens, such as soluble Aβ aggregates, in plasma and CSF by immunoassays, there is a possibility of interference by heterophilic antibodies (HA). In paper I, we show that HA generate false positive signals, by cross-binding the assay antibodies, when plasma and CSF from AD patients and healthy controls were analyzed for soluble Aβ aggregates, using sandwich ELISAs.

Natural anti-Aβ antibodies exist in AD patients and healthy individuals. Circulating Aβ and anti-Aβ antibodies may form immune complexes, masking epitopes on the anti-Aβ antibody, which makes the anti-Aβ antibody concentration difficult to measure. In paper II, the ELISpot technique enabled us to successfully measure B cell production of anti-Aβ antibodies. Our results show that anti-Aβ protofibril antibody production is present in both AD patients and healthy individuals, but is significantly higher in AD patients, indicating that the immune system attempt to eliminate the toxic Aβ species.

Insufficient lysosomal degradation is proposed to cause sporadic AD. In paper III, we used a co-culture system of astrocytes, neurons and oligodendrocytes, to clarify the role of astrocytes in Aβ protofibril clearance. Astrocytes are the most prominent glial cell type in the brain, but their role in AD remains elusive. We found that astrocytes effectively engulf, but inefficiently degrade Aβprotofibrils. This result in a high intracellular load of toxic, partly N-terminally truncated Aβ and lysosomal dysfunction. Moreover, we found that secretion of microvesicles, containing N-terminally truncated Aβ, induce neuronal apoptosis. In paper IV, we show that treatment with the protofibril selective antibody mAb158 lead to enhanced Aβ clearance and thereby prevent Aβ neurotoxicity.

Taken together, this thesis contributes with important knowledge on the role of Aβ protofibrils in AD pathogenesis and technical aspects that should be considered when measuring Aβ in human tissues.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1147
Keyword
Alzheimer's Disease, Amyloid-beta, Protofibrils, ELISA, ELISpot, Astrocyte, Monoclonal Antibody, Immunofluorescence
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-264647 (URN)978-91-554-9373-8 (ISBN)
Public defence
2015-12-04, Rudbecksalen, Rudbeckslaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2015-11-13 Created: 2015-10-15 Last updated: 2016-01-14Bibliographically approved

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