Figure 1 APP processing scheme lumen cytosol
Dominant genetic mutations known to cause early-onset AD all increase the production of Ap42 (5). These mutations occur in three genes: those encoding APP and the multi-pass membrane proteins presenilin-1 (PS1) and presenilin-2 (PS2). AD-causing missense mutations in APP are found near the p- and y-secretase cleavage sites that generate Ap. A double mutation found at the P2-P1 position of the p-secretase cleavage site is more efficiently processed by this protease, increasing production of C99 and therefore of all Ap peptides, including Ap42. Various single mutations near the y-secretase cleavage sites lead to specific increases in the levels of Ap42. Nearly 100 AD-causing missense mutations in the presenilins have been identified to date, and all those examined likewise specifically increase Ap42 production (6). These findings provided strong genetic evidence for the amyloid hypothesis of AD and particularly pointed to Ap42 as the primary molecular culprit.
Ap-based strategies for the discovery and development of AD therapeutics can focus on the production, assembly, or neurotoxicity of this peptide (7). Although each of these three approaches has its unique advantages and is being actively pursued, this chapter deals strictly with inhibitors for p- and y-secretases reported since 2000. Inhibitors identified prior to this are discussed in a previous Report (8).
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