Models of APP processing by the various secretases. (A) Processing of APP by α-, β-, and γ-secretases. (B) Current model of γ-secretase substrate processing in which the ectodomain shedding and the intramembrane cleavages are assumed to be separated spatially and temporally. (C) Proposed new model of γ-secretase processing based on all data herein in which the principal sheddase (α-/β-secretase) exists in an HMW complex with γ-secretase that accepts full-length substrates for rapid sequential processing.