A presenilin-1-dependent gamma-secretase-like protease mediates release ofNotch intracellular domain

Signalling through the receptor protein Notch, which is involved in crucial cell-fate decisions during development, requires ligand-induced cleavage o f Notch. This cleavage occurs within the predicted transmembrane domain, re leasing the Notch intracellular domain (MCD), and is reminiscent of gamma-s ecsretase-mediated cleavage of beta-amyloid precursor protein (APP), a crit ical event in the pathogenesis of Alzheimer's disease. a deficiency in pres enilin-1 (PS1) inhibits processing of APP by gamma-secretase in mammalian c ells, and genetic interactions between Notch and PS1 homologues in Caenorha bditis elegans indicate that the presenilins may modulate the Notch signall ing pathway(1-4). Here we report that, in mammalian cells, PS1 deficiency a lso reduces the proteolytic release of NICD from a truncated Notch construc t, thus identifying the specific biochemical step of the Notch signalling p athway that is affected by PS1. Moreover, several gamma-secretase inhibitor s block this same step in Notch processing indicating that related protease activities are responsible for cleavage within the predicted transmembrane domains of Notch and APP. Thus the targeting of gamma-secretase for the tr eatment of Alzheimer's disease may risk toxicity caused by reduced Notch si gnalling.