of the aspartyl protease γ-secretase complex that cleaves numerous membrane proteins intramembranously, including APP [(De Strooper, 2003) for review see (Selkoe and Wolfe, 2007)]. APP can undergo regulated intramembrane proteolysis (RIP) in at least two pathways known as the non-amyloidogenic and amyloidogenic pathways. In the former, APP first undergoes ectodomain shedding by an enzymatic activity termed α-secretase. While the identity of α-secretase is not fully known, members of the ADAM family and matrix metalloproteases ADAM10 and ADAM17, as well as the aspartyl protease BACE 2 exhibit α-secretase activity in vivo, cleaving APP in the Aβ region. Hampering Aβ formation, this cleavage results in the release of soluble fragment of APP (sAPPα) and the generation of a membrane-bound carboxyl-terminal fragment (CTF) that undergoes a second cleavage event within its transmembrane domain (via RIP) by γ-secretase (see figure 1). γ-secretase is a unique membrane multicomponent protease complex, in which PS are the catalytic core of the enzyme. In the amyloidogenic pathway, APP ectodomain shedding is carried out by the aspartyl protease β-site APP cleaving enzyme I [(BACE1; also known as memapsin and Asp2) (Hussain et al., 1999; Sinha et al., 1999; Vassar et al., 1999; Lin et al., 2000; Yan et al.,
