Molecular cell biology of presenilins

Abstract

Alzheimer's disease (AD), the most common cause of dementia in the elderly, is a progressive neurodegenerative disorder characterized pathologically by the presence of senile plaques and neurofibrillary tangles in the brains of affected individuals. Senile plaques are composed of amyloid-β peptides (Aβ), a proteolytic derivative of the β-amyloid precursor protein (βAPP). A subset of AD is inherited as an autosomal dominant trait (familial AD, FAD). Mutations in genes encoding βAPP, presenilin (PS) 1 and PS2 are known to cause FAD. Genetic mutations in all three genes that cosegregate with FAD increase the production of the most amyloidogenic species, Aβ42. Moreover, PS1-deficient neurons exhibit severe defects in the production of Aβ, suggesting that PS1 plays an important role in γ-cleavage that liberates the C terminus of Aβ. The physiological role of PS is still unknown, but data from studies in C. elegans, Drosophila and PS1 knock out mice suggests that PS1 plays a crucial role in Notch signaling, and recently it was shown that PS1 is required for the proteolytic release of the intracellular domain of Notch following activation of Notch by its ligand. Further studies on PS-mediated intra- and jaxtamembranous proteolysis will lead to the understanding of the pathological mechanism of AD as well as of a novel mode of membrane protein processing.