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Inhibition of acyl-coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway

Henri J. Huttunen^*,,,1, Camilla Peach^*,,, Raja Bhattacharyya^*,,, Cory Barren^*,,, Warren Pettingell^*,,, Birgit Hutter-Paier^,, Manfred Windisch^,, Oksana Berezovska^, and Dora M. Kovacs^*,,,2

^* Neurobiology of Disease Laboratory, Genetics and Aging Research Unit,

MassGeneral Institute for Neurodegenerative Disease, and

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; and

JSW-Research Forschungslabor, Institute of Experimental Pharmacology, Grambach/Graz, Austria

² Correspondence: Neurobiology of Disease Laboratory, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA. E-mail: dora_kovacs{at}hms.harvard.edu

Amyloid β-peptide (Aβ) has a central role in the pathogenesis of Alzheimer’s disease (AD). Cellular cholesterol homeostasis regulates endoproteolytic 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 distribution, 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 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 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.

Key Words: Alzheimer’s disease • cholesterol • endoplasmic reticulum • lipid • protein maturation

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