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The excessive generation and accumulation of 40- and 42-aa β-amyloid peptides (Aβ₄₀/Aβ₄₂) in selectively vulnerable brain regions is a major neuropathological feature of Alzheimer’s disease. Aβ, derived by proteolytic cleavage from the β-amyloid precursor protein (βAPP), is normally secreted. However, recent evidence suggests that significant levels of Aβ also may remain inside cells. Here, we have investigated the subcellular compartments within which distinct amyloid species are generated and the compartments from which they are secreted. Three experimental approaches were used: (i) immunofluorescence performed in intact cortical neurons; (ii) sucrose gradient fractionation performed with mouse neuroblastoma cells stably expressing wild-type βAPP₆₉₅ (N2a₆₉₅); and (iii) cell-free reconstitution of Aβ generation and trafficking from N2a₆₉₅ cells. These studies demonstrate that: (i) Aβ₄₀ (Aβ_1–40 plus …