γ-Secretase Catalyzes Sequential Cleavages of the AβPP Transmembrane Domain

The biogenesis of the amyloid-beta peptide (A beta) is a central issue in Alzheimer's disease (AD) research. A beta is produced by beta- and gamma-secretases from the amyloid-beta protein precursor (A beta PP). These proteases are targets for the development of therapeutic compounds to downregulate A beta production. gamma-secretase has received more attention 1) because it generates the C-terminus of A beta, which is important in the pathogenesis of AD because the longer A beta species are more amyloidogenic, and 2) because it cleaves A beta PP within its transmembrane domain. In the understanding the mechanism of gamma-secretase cleavage, three major cleavage sites have been identified, namely, gamma-cleavage site at A beta(40/42), zeta-cleavage site at A beta(46), and epsilon-cleavage site at A beta(49). Moreover, the novel finding that some of the known gamma-secretase inhibitors inhibit the formation of secreted A beta(40) and A beta(42), but cause an intracellular accumulation of long A beta(46), provided information extremely important for the development of strategies aimed at the design of gamma-secretase inhibitors to prevent and treat AD. In addition, it has been established that the C-terminus of A beta is generated by a series of sequential cleavages: first, epsilon-cleavage, followed by gamma-cleavage and finally by gamma-cleavage, commencing from the membrane boundary to the middle of the A beta PP membrane domain.