Presenilins: multifunctional proteins involved in Alzheimer's disease pathology

Early-onset aggressive forms of Alzheimer's disease (AD) are of genetic nature and have been linked to inherited mutations located on chromosomes 21, 14, and 1. The gene products of chromosomes 14 and 1, which are responsible for most of these familial forms of the disease (FAD), have been recently identified and referred to as presenilin 1 and 2 (PS1, PS2), respectively. Several lines of evidence derived from neuropathological, cell biology, and transgenesis approaches indicate that PS could interfere with the processing of the beta-amyloid precursor protein (betaAPP). Thus, FAD-linked mutations in PS exacerbate the production of Abeta42, the readily aggregable Abeta species corresponding to one of the main constituents of the senile plaques that invade the cortical areas of affected brains. Recent studies indicate that PS functions could be intimately related with the susceptibility of PS to further processing by caspase-like enzymes and other unknown proteolytic activities. Here I briefly report on the post-translational events undergone by PS and examine recent advances concerning their possible roles in development, cell signaling, and apoptosis. Possible alterations brought by FAD-linked mutations will be discussed.