Dysfunctional γ-Secretase in Familial Alzheimer’s Disease
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Issue Date
2019-01-01Author
Wolfe, Michael S.
Publisher
Springer Verlag
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
© Springer Science+Business Media, LLC, part of Springer Nature 2018
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Show full item recordAbstract
Genetics strongly implicate the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimer’s disease. Dominant missense mutation in the presenilins and the amyloid precursor protein (APP) cause early-onset familial Alzheimer’s disease (FAD). As presenilin is the catalytic component of the γ-secretase protease complex that produces Aβ from APP, mutation of the enzyme or substrate that produce Aβ leads to FAD. However, the mechanism by which presenilin mutations cause FAD has been controversial, with gain of function and loss of function offered as binary choices. This overview will instead present the case that presenilins are dysfunctional in FAD. γ-Secretase is a multi-functional enzyme that proteolyzes the APP transmembrane domain in a complex and processive manner. Reduction in a specific function—the carboxypeptidase trimming of initially formed long Aβ peptides containing most of the transmembrane domain to shorter secreted forms—is an emerging common feature of FAD-mutant γ-secretase complexes.
Description
This is a post-peer-review, pre-copyedit version of an article published in Neurochemical Research. The final authenticated version is available online at: http://dx.doi.org/10.1007/s11064-018-2511-1.
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Citation
Wolfe M. S. (2019). Dysfunctional γ-Secretase in Familial Alzheimer's Disease. Neurochemical research, 44(1), 5–11. doi:10.1007/s11064-018-2511-1
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