Premium
Inhibition of acyl‐coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway
Author(s) -
Huttunen Henri J.,
Peach Camilla,
Bhattacharyya Raja,
Barren Cory,
Pettingell Warren,
Hutter-Paier Birgit,
Windisch Manfred,
Berezovska Oksana,
Kovacs Dora M.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-134999
Subject(s) - amyloid precursor protein , endoplasmic reticulum , unfolded protein response , presenilin , microbiology and biotechnology , biochemistry , senile plaques , chemistry , biology , medicine , alzheimer's disease , disease
Amyloid β‐peptide (Aβ) has a central role in the pathogenesis of Alzheimer's disease (AD). Cellular cholesterol homeostasis regulates endoproteo‐ lytic generation of Aβ from the amyloid precursor protein (APP). Previous studies have identified acyl‐ coenzyme A: cholesterol acyltransferase (ACAT)’ an enzyme that regulates subcellular cholesterol distribu‐tion, as a potential therapeutic target for AD. Inhibition of ACAT activity decreases Aβ 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 deg‐radation 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 Aβ levels in individual animals. Our results identify a novel ACAT‐dependent mechanism that regulates secretory trafficking of APP, likely contributing to decreased Aβ 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