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The Arctic mutation interferes with processing of the amyloid precursor protein
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
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2002 In: Neuroreport, ISSN 0959-4965, Vol. 13, no 15, 1857-1860 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2002. Vol. 13, no 15, 1857-1860 p.
URN: urn:nbn:se:uu:diva-95484OAI: oai:DiVA.org:uu-95484DiVA: diva2:169717
Available from: 2007-03-02 Created: 2007-03-02Bibliographically approved
In thesis
1. Pathogenic Mechanisms of the Arctic Alzheimer Mutation
Open this publication in new window or tab >>Pathogenic Mechanisms of the Arctic Alzheimer Mutation
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, neuropathologically characterized by neurofibrillay tangles and deposition of amyloid-β (Aβ) peptides. Several mutations in the gene for amyloid precursor protein (APP) cause familial AD and affect APP processing leading to increased levels of Aβ42. However, the Arctic Alzheimer mutation (APP E693G) reduces Aβ levels. Instead, the increased tendency of Arctic Aβ peptides to form Aβ protofibrils is thought to contribute to the pathogenesis.

In this thesis, the pathogenic mechanisms of the Arctic mutation were further investigated, specifically addressing if and how the mutation affects APP processing. Evidence of a shift towards β-secretase cleavage of Arctic APP was demonstrated. Arctic APP did not appear to be an inferior substrate for α-secretase, but the availability of Arctic APP for α-secretase cleavage was reduced, with diminished levels of cell surface APP in Arctic cells. Interestingly, administration of the fatty acid docosahexaenoic acid (DHA) stimulated α-secretase cleavage and partly reversed the effects of the Arctic mutation on APP processing.

In contrast to previous findings, the Arctic mutation generated enhanced total Aβ levels suggesting increased Aβ production. Importantly, this thesis illustrates and explains why measures of both Arctic and wild type Aβ levels are highly dependent upon the Aβ assay used, with enzyme-linked immunosorbent assay (ELISA) and Western blot generating different results. It was shown that these differences were due to inefficient detection of Aβ oligomers by ELISA leading to an underestimation of total Aβ levels.

In conclusion, the Arctic APP mutation leads to AD by multiple mechanisms. It facilitates protofibril formation, but it also alters trafficking and processing of APP which leads to increased steady state levels of total Aβ, in particular at intracellular locations. Importantly, these studies highlight mechanisms, other than enhanced production of Aβ peptide monomers, which could be implicated in sporadic AD.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 59 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 229
Neurosciences, Alzheimer's disease, Arctic mutation, Amyloid precursor protein, Amyloid-β, APP processing, Aβ oligomers, Docosahexaenoic acid, Neurovetenskap
urn:nbn:se:uu:diva-7582 (URN)978-91-554-6806-4 (ISBN)
Public defence
2007-03-23, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15
Available from: 2007-03-02 Created: 2007-03-02 Last updated: 2013-06-18Bibliographically approved

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