APP and Alzheimer disease: In the amyloidogenic processing pathway, APP is internalized to early endosomes through Fe65 and is cleaved by β-secretase to generate soluble sAPPβ and a C-terminal fragment, C99; C99 is further cleaved by γ-secretase in late endosomes to generate the ACID and intact Aβ, inducing Aβ pathology, which is elevated in AD (Selkoe et al., 1996; Wolfe et al., 1999; Yan et al., 1999; Cai et al., 2001; Hardy and Selkoe, 2002; Thinakaran and Koo, 2008).