NDLI: Familial Alzheimer's disease mutations inhibit γ-secretase-mediated liberation of β-amyloid precursor protein carboxy-terminal fragment

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Familial Alzheimer's disease mutations inhibit γ-secretase-mediated liberation of β-amyloid precursor protein carboxy-terminal fragment

Content Provider	Scilit
Author	Wiley, Jesse C. Hudson, Mark Kanning, Kevin C. Schecterson, Leslyanne C. Bothwell, Mark
Copyright Year	2005
Description	Journal: Journal of Neurochemistry Cleavage of the beta-secretase processed beta-amyloid precursor protein by gamma-secretase leads to the extracellular release of Abeta42, the more amyloidogenic form of the beta-amyloid peptide, which subsequently forms the amyloid-plaques diagnostic of Alzheimer's disease. Mutations in beta-amyloid precursor protein (APP), presenilin-1 and presenilin-2 associated with familial Alzheimer's disease (FAD) increase release of Abeta42, suggesting that FAD may directly result from increased gamma-secretase activity. Here, we show that familial Alzheimer's disease mutations clustered near the sites of gamma-secretase cleavage actually decrease gamma-secretase-mediated release of the intracellular fragment of APP (CTFgamma). Concordantly, presenilin-1 mutations that result in Alzheimer's disease also decrease the release of CTFgamma. Mutagenesis of the epsilon cleavage site in APP mimicked the effects of the FAD mutations, both decreasing CTFgamma release and increasing Abeta42 production, suggesting that perturbation of this site may account for the observed decrement in gamma-secretase-mediated proteolysis of APP. As CTFgamma has been implicated in transcriptional activation, these data indicate that decreased signaling and transcriptional regulation resulting from FAD mutations in beta-amyloid precursor protein and presenilin-1 may contribute to the pathology of Alzheimer's disease.
Related Links	http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2005.03266.x/pdf
Ending Page	1201
Page Count	13
Starting Page	1189
e-ISSN	14714159
DOI	10.1111/j.1471-4159.2005.03266.x
Journal	Journal of Neurochemistry
Issue Number	5
Volume Number	94
Language	English
Publisher	Wiley-Blackwell
Publisher Date	2005-09-01
Access Restriction	Open
Subject Keyword	Journal: Journal of Neurochemistry Biochemistry and Molecular Biology Alzheimer's Disease Β‐amyloid Precursor Protein Familial Alzheimer's Disease
Content Type	Text
Resource Type	Article

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