Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer's disease

The amyloid-beta protein (A beta) is strongly implicated in the pathogenesi s of Alzheimer's disease. The final step in the production of A beta from t he amyloid precursor protein (APP) is proteolysis by the unidentified gamma -secretases. This cleavage event is unusual in that it apparently occurs wi thin the transmembrane region of the substrate. Studies with substrate-base d inhibitors together with molecular modeling and mutagenesis of the gamma- secretase cleavage site of APP suggest that gamma-secretases are aspartyl p roteases that catalyze a novel intramembranous proteolysis. This proteolysi s requires the presenilins, proteins with eight transmembrane domains that are mutated in most cases of autosomal dominant familial Alzheimer's diseas e. Two conserved transmembrane aspartates in presenilins are essential for gamma-secretase activity, suggesting that presenilins themselves are gamma- secretases, Moreover, presenilins also mediate the apparently intramembrano us cleavage of the Notch receptor, an event critical for Notch signaling an d embryonic development. Thus, if presenilins are gamma-secretases, then th ey are also likely the proteases that cleave Notch within its transmembrane domain. Another protease, S2P, involved in the processing of the sterol re gulatory element binding protein, is also a multipass integral membrane pro tein which cleaves within or very close to the transmembrane region of its substrate. Thus, presenilins and S2P appear to be members of a new type of polytopic protease with an intramembranous active site.