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

Deposition of aggregated amyloid beta-protein (A beta), 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 A beta polymerization in vivo. Here, we report that a seeding A beta, which catalyzes the fibrillogenesis of soluble A beta, is generated from the apically missorted amyloid precursor protein in cultured epithelial cells. Furthermore, the generation of this A beta depends exclusively on the presence of cholesterol in the cells. Taken together with mass spectrometric analysis of this novel A beta and our recent study (3), it is suggested that a conformationally altered form of A beta, which acts as a "seed" for amyloid fibril formation, is generated in intracellular cholesterol-rich microdomains.