Characterization of a presenilin-mediated amyloid precursor protein carboxyl-terminal fragment γ: Evidence for distinct mechanisms involved in γ-secretase processing of the APP and Notch1 transmembrane domains

A variety of investigations have led to the conclusion that presenilins (PS) play a critical role in intramembranous, γ-secretase proteolysis of selected type I membrane proteins, including Notchl and amyloid precursor protein (APP). We now show that the generation of the S3/Notch intracellular domain and APP-carboxyl-terminal fragment γ (CTFγ) derivatives are dependent on PS expression and inhibited by a highly selective and potent γ-secretase inhibitor. Unexpectedly, the APP-CTFγ derivative is generated by processing between Leu-645 and Val-646 (of APP₆₉₅), several amino acids carboxyl-terminal to the scissile bonds for production of amyloid β protein peptides. Although the relationship of APP-CTFγ to the production of amyloid β protein peptides is not known, we conclude that in contrast to the highly selective PS-dependent processing of Notch, the PS-dependent γ-secretase processing of APP is largely nonselective and occurs at multiple sites within the APP transmembrane domain.