APP metabolism by the secretase enzymes. APP is sequentially cleaved by BACE1, the β-secretase, and γ-secretase, a complex comprised of presenilin, nicastin, Aph1 and Pen2, to generate Aβ. BACE1 cleavage of APP is a prerequisite for Aβ formation and is putatively the rate-limiting step in Aβ genesis. BACE1 cleavage of APP forms the N-terminus of the peptide, and two cleavage fragments are liberated: APPsβ, a secreted ectodomain, and C99, a membrane bound fragment. C99 is the substrate for γ-secretase, and C99 cleavage generates the AICD together with the C-terminus of Aβ. Aβ formation is prevented by the activities of α-secretase, which has been identified as TACE, ADAM9 and ADAM10. α-secretase cleaves APP to generate the secreted ectodomain, APPsα and membrane bound fragment, C83. C83 is subsequently cleaved by the γ-secretase complex to yield the 3 KDa fragment, P3 and the AICD.