Figure 1.

A schematic diagram of amyloid β precursor protein (APP) proteolytic processing (not drawn to scale). APP is a large transmembrane molecule (unboxed at top). There is a large extracellular or luminal domain with β- and α-secretase cleavage sites (β and α, respectively) close to the membrane. The γ-secretase sites (γ) occur within the transmembrane region. On proteolytic processing the ectodomain is first shed by either α- or β-secretase mediated cleavage (middle, left and right boxes, respectively). Cleavage by α-secretase (box at middle left) releases APPsα extracellularily or luminally and leaves a C83 (also known as CTFα) stub in the membrane. Cleavage by β-secretase (box at middle right) releases APPsβ extracellularly or luminally and leaves a C99 (also known as CTFβ) stub in the membrane. Regulated intramembrane proteolysis (RIP) by γ-secretase subsequently cleaves the stubs remaining in the membrane (bottom). Cleavage of C83 (box on bottom left) liberates p3 and the APP intracellular domain (AICD). Cleavage of C99 (box on the bottom right) liberates amyloid β peptide (Aβ) and the APP intracellular domain (AICD).