Secretion of β-amyloid precursor protein cleaved at the amino terminus of the β-amyloid peptide

THE accumulation in brain of senile plaques containing β-amyloid protein (Aβ) is a defining feature of Alzheimer's disease^1-3. The amyloid precursor protein (APP)⁴ from which Aβ is derived is subject to several genetic mutations which segregate with rare familial forms of the disease, resulting in early onset of dementia and plaque formation ^5-9, suggesting that APP metabolism plays a causal role in the disease. Various cell types have been shown to release a soluble form of Aβ, thus allowing for the in vitro study of Aβ generation ^10-12. We report here evidence that a substantial portion of the APP secreted by human mixed brain cell cultures, as well as that present in cerebrospinal fluid, is of a novel form cleaved precisely at the amino terminus of Aβ, suggesting that a secretory pathway is involved in Aβ genesis.