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

Tetsuya Mizuno, Makoto Nakata, Hironobu Naiki, Makoto Michikawa, Rong Wang, Christian Haass, Katsuhiko Yanagisawa

Research output: Contribution to journalArticlepeer-review

112 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)15110-15114
Number of pages5
JournalJournal of Biological Chemistry
Volume274
Issue number21
DOIs
StatePublished - 21 May 1999
Externally publishedYes

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