γ-Secretase Catalyzes Sequential Cleavages of the AβPP Transmembrane Domain

The biogenesis of the amyloid-β peptide (Aβ) is a central issue in Alzheimer's disease (AD) research. Aβ is produced by β- and γ-secretases from the amyloid-β protein precursor (AβPP). These proteases are targets for the development of therapeutic compounds to downregulate Aβ production. γ-secretase has received more attention 1) because it generates the C-terminus of Aβ, which is important in the pathogenesis of AD because the longer Aβ species are more amyloidogenic, and 2) because it cleaves AβPP within its transmembrane domain. In the understanding the mechanism of γ-secretase cleavage, three major cleavage sites have been identified, namely, γ-cleavage site at Aβ_40/42, ζ-cleavage site at Aβ₄₆, and ε-cleavage site at Aβ₄₉. Moreover, the novel finding that some of the known γ-secretase inhibitors inhibit the formation of secreted Aβ₄₀ and Aβ₄₂, but cause an intracellular accumulation of long Aβ₄₆, provided information extremely important for the development of strategies aimed at the design of γ-secretase inhibitors to prevent and treat AD. In addition, it has been established that the C-terminus of Aβ is generated by a series of sequential cleavages: first, ε-cleavage, followed by ζ-cleavage and finally by γ-cleavage, commencing from the membrane boundary to the middle of the AβPP membrane domain.