Figure 1. Proteolytic processing of the amyloid precursor protein (APP).

APP is processed by either of two pathways. First, the large extracellular domain is removed by either α-(left) or β-secretase (right) in a processed termed “ectodomain shedding” to release the soluble APP ectodomain (sAPPα and sAPPβ, respectively) into the extracellular space. The resulting APP C-terminal stubs (C83 and C99, respectively) can then serve as substrates for intramembranous cleavage by γ-secretase. Cleavage of C83 generates the p3 peptide and the APP intracellular domain (AICD), whereas cleavage of C99 generates the Aβ peptide and AICD. p3 and Aβ are ultimately released into the extracellular space, whereas AICD remains in the cytosol. Note that cleavage of APP by α-secretase precludes formation of Aβ.