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J Biol Chem, Vol. 274, Issue 21, 15110-15114, May 21, 1999

Cholesterol-dependent Generation of a Seeding Amyloid -Protein in Cell Culture

Tetsuya Mizuno, Makoto Nakata^§, Hironobu Naiki^¶, Makoto Michikawa, Rong Wang, Christian Haass^**, and Katsuhiko Yanagisawa

From the  Department of Dementia Research, National Institute for Longevity Sciences, Gengo 36-3, Morioka, Obu, 474-8522, Japan, ^§ Protein Research Foundation, Peptide Institute, Inc., 4-1-2 Ina, Minoh, Osaka 562, Japan, ^¶ Department of Pathology, Fukui Medical University, Fukui 910-1193, Japan,  Laboratory for Mass Spectrometry, Rockefeller University, New York, New York 10021-6399, and ^** Department of Molecular Biology, J5, Central Institute for Mental Health, 68159 Mannheim, Germany

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

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