Zinc metalloprotease activity in APP processing. (a) In the amyloidogenic pathway, the transmembrane APP is cleaved first by β-secretase (β) to form the soluble sAPPβ and the membrane-bound C99, which in turn is cleaved by γ-secretase (γ) to form AICD and the amyloidogenic Aβ peptides. The Aβ peptides are degraded by a number of zinc metalloproteases including NEP and IDE. In the nonamyloidogenic pathway, APP is cleaved first by the α-secretase (α) (zinc metalloprotease) to form the soluble sAPPα and the membrane bound C83, which is then cleaved by γ-secretase (γ) to form p3 and AICD. Zinc metalloproteases depicted in red. Representative amino acids from the degradation of Aβ are shown in single letter code. (b) Action of zinc metalloproteases on monomeric and aggregated forms of Aβ (modified from [43]). Aβ: Amyloid β; AICD: APP intracellular domain; APP: Amyloid precursor protein; ECE: Endothelin-converting enzyme; IDE: Insulin degrading enzyme; MMP: Matrix metalloprotease; NEP: Neprilysin.
