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Processive proteolysis of APP substrate by γ-secretase. Initial endoproteolysis at the ε cleavage site of APP substrate C99 results in Aβ48 or Aβ49 and corresponding APP intracellular domain fragments AICD49-99 and AICD50-99. The carboxypeptidase activity of γ-secretase then trims the initial Aβ peptides along two pathways: Aβ49→Aβ46→Aβ43→Aβ40 and Aβ48→Aβ45→Aβ42→Aβ38.
