An APP inhibitory domain containing the Flemish mutation residue modulates gamma-secretase activity for Abeta production.

Gamma-secretase is an aspartyl protease that cleaves multiple substrates within their transmembrane domains. Gamma-secretase processes the amyloid precursor protein (APP) to generate gamma-amyloid (Agamma) peptides associated with Alzheimer's disease. Here, we show that APP possesses a substrate inhibitory domain (ASID) that negatively modulates gamma-secretase activity for Agamma production by binding to an allosteric site within the gamma-secretase complex. Alteration of this ASID by deletion or mutation, as is seen with the Flemish mutation (A21G), reduces its inhibitory potency and promotes Agamma production. Notably, peptides derived from ASID show selective inhibition of gamma-secretase activity for Agamma production over Notch1 processing. Therefore, this mode of regulation represents an unprecedented mechanism for modulating gamma-secretase, providing insight into the molecular basis of Alzheimer's disease pathogenesis and a potential strategy for the development of therapeutics.