APP is a type 1 transmembrane glycoprotein. The majority of APP is processed by the non-amyloidogenic pathway (thick arrow) APP is first cleaved by a-secretase within the amyloid-βprotein (Aβ) domain leading to APPsαsecretion and precluded Aβ generation. Membrane anchored α-carboxy terminal fragment (CTF) is then cleaved by γ-secretase within the membrane releasing the p3 peptide and the APP intracellular domain (AICD). Alternatively amyloidgenesis takes place when APP is first cleaved by β-secretase, producing APPsβ. Aβ and AICD are generated upon cleavage by γ-secretase of the β-CTF fragment retained in the membrane