Role of presenilin in gamma-secretase cleavage of amyloid precursor protein

Cerebral accumulation of the amyloid beta-protein (A beta) is an early and invariant event in the pathogenesis of Alzheimer's disease (AD). Mutations in the presenilin (PS) 1 and 2 genes that increase production of the highly amyloidogenic A beta(42) are the most common cause of familial AD. Deletio n of PS1 in mice reduces A beta generation, indicating that PS1 mediates th e last step in the generation of A beta from beta-amyloid precursor protein (APP) by the unidentified gamma-secretase. Mutating either of two conserve d transmembrane aspartates in PS 1 significantly reduced A beta production and increased the APP C-terminal fragments that are gamma-secretase substra tes. These results indicate that PS1 is either a unique diaspartyl cofactor for gamma-secretase or is itself gamma-secretase. Furthermore, studies on the gamma-secretase-like proteolytic processing of Notch and Ire1 suggest a common mechanism for the involvement of PS1 in intramembrane proteolysis o f membrane proteins, (C) 2000 Elsevier Science Inc. All rights reserved.