Figure 1. APP processing in AD. In early Alzheimer's disease pathogenesis, amyloid precursor protein (APP) is processed by a series of proteases to yield several neurotoxic protein fragments. First, APP is cut by b-site APP-cleaving enzyme 1 (BACE1) [a] to yield a fragment called C99 [b], which is subsequently cut by the g-secretase complex [c] to yield b-amyloid (Ab).

Lauritzen et al. have provided in vivo evidence in a mouse model of AD that suggests intracellular C99 accumulation contributes to early AD pathology. Thathiah et al. have shown that arrestin b2 (ARRB2) acts as a g-secretase cofactor that specifically regulates the processing of C99.