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Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. doi: 10.1073/pnas.1618657114. Epub 2016 Dec 5.

Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase.

Author information

1
Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
2
Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China shi-lab@tsinghua.edu.cn.

Abstract

A hallmark of Alzheimer's disease (AD) is the aggregation of β-amyloid peptides (Aβ) into amyloid plaques in patient brain. Cleavage of amyloid precursor protein (APP) by the intramembrane protease γ-secretase produces Aβ of varying lengths, of which longer peptides such as Aβ42 are thought to be more harmful. Increased ratios of longer Aβs over shorter ones, exemplified by the ratio of Aβ42 over Aβ40, may lead to formation of amyloid plaques and consequent development of AD. In this study, we analyzed 138 reported mutations in human presenilin-1 (PS1) by individually reconstituting the mutant PS1 proteins into anterior-pharynx-defective protein 1 (APH-1)aL-containing γ-secretases and examining their abilities to produce Aβ42 and Aβ40 in vitro. About 90% of these mutations lead to reduced production of Aβ42 and Aβ40. Notably, 10% of these mutations result in decreased Aβ42/Aβ40 ratios. There is no statistically significant correlation between the Aβ42/Aβ40 ratio produced by a γ-secretase variant containing a specific PS1 mutation and the mean age at onset of patients from whom the mutation was isolated.

KEYWORDS:

Alzheimer’s disease; Aβ peptides; amyloid hypothesis; cleavage activity; γ-secretase

Comment in

PMID:
27930341
PMCID:
PMC5278480
DOI:
10.1073/pnas.1618657114
[Indexed for MEDLINE]
Free PMC Article

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