Identification of the role of presenilins beyond Alzheimer's disease

Mutations in the genes encoding presenilin 1 (PS1) and presenilin 2 (PS2) account for the majority of the cases of familial early-onset Alzheimer's disease (FAD). Presenilins (PSs) facilitate the intramembraneous cleavage of amyloid precursor protein (APP), coined gamma-secretase cleavage, which generates beta-amyloid peptides (Abeta). Considerable evidence suggests that FAD-linked PS variants exert their pathogenic influence by selectively elevating the levels of highly fibrillogenic Abeta42 peptides. In addition, numerous other functions have been ascribed to PSs based on subcellular localization, protein interactions, loss of function studies, and intramembraneous gamma-secretase cleavage of growing number of substrates. This review summarizes the diverse physiological functions that are regulated by PSs beyond APP metabolism. (C) 2004 Elsevier Ltd. All rights reserved.