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

A hallmark of Alzheimer's disease (AD) is the aggregation of gamma-amyloid peptides (A beta) into amyloid plaques in patient brain. Cleavage of amyloid precursor protein (APP) by the intramembrane protease gamma-secretase produces A beta of varying lengths, of which longer peptides such as A beta 42 are thought to be more harmful. Increased ratios of longer A beta s over shorter ones, exemplified by the ratio of A beta 42 over A beta 40, 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 gamma-secretases and examining their abilities to produce A beta 42 and A beta 40 in vitro. About 90% of these mutations lead to reduced production of A beta 42 and A beta 40. Notably, 10% of these mutations result in decreased A beta 42/A beta 40 ratios. There is no statistically significant correlation between the A beta 42/A beta 40 ratio produced by a gamma-secretase variant containing a specific PS1 mutation and the mean age at onset of patients from whom the mutation was isolated.