APP processing and Aβ accumulation. Mature APP (center, inside dashed box) is metabolized by 2 competing pathways, the α-secretase pathway that generates sAPPα and C83 (also known as CTFα; left) and the β-secretase pathway that generates sAPPβ and C99 (right). Some β-secretase cleavage is displaced by 10 amino acid residues and generates sAPPβ′ and C89 (see Figure 4). All carboxyterminal fragments (C83, C99, and C89) are substrates for γ-secretase, generating the APP intracellular domain (AICD) and, respectively, the secreted peptides p3 (not shown), Aβ (right), and Glu11 Aβ (see Figure 4). Aβ aggregates into small multimers (dimers, trimers, etc.) known as oligomers. Oligomers appear to be the most potent neurotoxins, while the end stage senile plaque is relatively inert.