Cholesterol-dependent generation of a seeding amyloid β-protein in cell culture

Deposition of aggregated amyloid β-protein (Aβ), a proteolytic cleavage product of the amyloid precursor protein (1), is a critical step in the development of Alzheimer's disease (2). However, we are far from understanding the molecular mechanisms underlying the initiation of Aβ polymerization in vivo. Here, we report that a seeding Aβ, which catalyzes the fibrillogenesis of soluble Aβ, is generated from the apically missorted amyloid precursor protein in cultured epithelial cells. Furthermore, the generation of this Aβ depends exclusively on the presence of cholesterol in the cells. Taken together with mass spectrometric analysis of this novel Aβ and our recent study (3), it is suggested that a conformationally altered form of Aβ, which acts as a 'seed' for amyloid fibril formation, is generated in intracellular cholesterol-rich microdomains.