β-Amyloid precursor protein processing. β-Amyloid precursor protein (APP) can be cleaved via two pathways, the nonamyloidogenic pathway (left, green) or the amyloidogenic pathway (right, red). Under normal conditions, the majority of APP is cleaved within the amyloid-β (Aβ) domain by α-secretase to produce secreted APP (sAPP)α and membrane-bound C83. C83 can be further cleaved by γ-secretase, producing extracellular fragment p3 and intracellular carboxy-terminal fragment (CTF)γ. In the amyloidogenic pathway, APP is first cleaved by β-secretase to produce sAPPβ and membrane-bound C99. Cleavage of C99 by γ-secretase yields Aβ and intracellular CTFγ. γ-Secretase cleaves APP at multiple sites close to the inner membrane leaflet to produce variants of Aβ peptide with different lengths. The 42 amino acid Aβ peptide, Aβ42 (after γ-cleavage indicated in the figure), is considered the major toxic Aβ in Alzheimer’s disease. Insoluble Aβ is deposited and aggregates to form the core of neuritic plaques in the brain, the pathological hallmark of Alzheimer’s disease.