Analysis of 138 pathogenic mutations in presenilin 1 on the in vitro production of Ab42 and Ab40 peptides by g secretase
Significance Alzheimer's disease (AD) is the most common form of dementia, but the cause of AD remains poorly understood. Using highly purified recombinant g secretase, we examined the effect of 138 AD derived presenilin 1 (PS1) mutations on the production of b amyloid peptides (Ab42 and Ab40) These 138 mutations cover virtually all AD targeted amino acids in PS1. Our results reveal no significant correlation between the Ab42/Ab40 ratio produced by a g secretase variant with a specific PS1 mutation and the mean age at onset of patients carrying this mutation. The comprehensive characterization of pathogenic PS1 mutations serves as a valuable resource for the analysis of g secretase activities and AD pathogenesis. A hallmark of Alzheimer's disease (AD) is the aggregation of b amyloid peptides (Ab) into amyloid plaques in patient brain. Cleavage of amyloid precursor protein (APP) by the intramembrane protease g secretase produces Ab of varying lengths, of which longer peptides such as Ab42 are thought to be more harmful. Increased ratios of longer Abs over shorter ones, exemplified by the ratio of Ab42 over Ab40, 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 g secretases and examining their abilities to produce Ab42 and Ab40 in vitro. About 90% of these mutations lead to reduced production of Ab42 and Ab40. Notably, 10% of these mutations result in decreased Ab42/Ab40 ratios. There is no statistically significant correlation between the Ab42/Ab40 ratio produced by a g secretase variant containing a specific PS1 mutation and the mean age at onset of patients from whom the mutation was isolated.
Proceedings of the National Academy of Sciences