Figure 2.
Processive proteolysis by γ-secretase. The protease first carries out endoproteolysis (ε) near the cytosolic end of the TMD of the APP substrate, with release of the intracellular domain (AICD). This is followed by carboxypeptidase cleavages (ζ, γ, and γ′) of the remaining long Aβ peptides, in intervals of roughly three amino acids, to secreted peptides that are 38–43 residues in length. There are two general pathways for Aβ generation: Aβ49 → Aβ46 → Aβ43 → Aβ40 and Aβ48 → Aβ45 → Aβ42 → Aβ38.