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

Cerebral accumulation of the amyloid β-protein (Aβ) 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 Aβ₄₂ are the most common cause of familial AD. Deletion of PS1 in mice reduces Aβ generation, indicating that PS1 mediates the last step in the generation of Aβ from β-amyloid precursor protein (APP) by the unidentified γ-secretase. Mutating either of two conserved transmembrane aspartates in PS1 significantly reduced Aβ production and increased the APP C-terminal fragments that are γ-secretase substrates. These results indicate that PS1 is either a unique diaspartyl cofactor for γ-secretase or is itself γ-secretase. Furthermore, studies on the γ-secretase-like proteolytic processing of Notch and Ire1 suggest a common mechanism for the involvement of PS1 in intramembrane proteolysis of membrane proteins. (C) 2000 Elsevier Science Inc.