期刊
FASEB JOURNAL
卷 23, 期 11, 页码 3819-3828出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.09-134999
关键词
Alzheimer's disease; cholesterol; endoplasmic reticulum; lipid; protein maturation
资金
- Cure Alzheimer's Fund
- U.S. National Institutes of Health [R01 NS45860]
- Helsingin Sanomat Centennial Foundation
- Maud Kuistila Foundation [CI-1011, CP-113,818]
Amyloid beta-peptide (A beta) has a central role in the pathogenesis of Alzheimer's disease (AD). Cellular cholesterol homeostasis regulates endoproteolytic generation of A beta from the amyloid precursor protein (APP). Previous studies have identified acylcoenzyme A: cholesterol acyltransferase (ACAT), an enzyme that regulates subcellular cholesterol distribution, as a potential therapeutic target for AD. Inhibition of ACAT activity decreases A beta generation in cell-and animal-based models of AD through an unknown mechanism. Here we show that ACAT inhibition retains a fraction of APP molecules in the early secretory pathway, limiting the availability of APP for secretase-mediated proteolytic processing. ACAT inhibitors delayed the trafficking of immature APP molecules from the endoplasmic reticulum (ER) as shown by metabolic labeling and live-cell imaging. This resulted in partial ER retention of APP and enhanced ER-associated degradation of APP by the proteasome, without activation of the unfolded protein response pathway. The ratio of mature APP to immature APP was reduced in brains of mice treated with ACAT inhibitors, and strongly correlated with reduced brain APP-C99 and cerebrospinal fluid A beta levels in individual animals. Our results identify a novel ACAT-dependent mechanism that regulates secretory trafficking of APP, likely contributing to decreased A beta generation in vivo.-Huttunen, H. J., Peach, C., Bhattacharyya, R., Barren, C., Pettingell, W., Hutter-Paier, B., Windisch, M., Berezovska, O., Kovacs, D. M. Inhibition of acyl-coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway. FASEB J. 23, 3819-3828 (2009). www.fasebj.org
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