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J Biol Chem. 2012 Mar 9;287(11):8424-33. doi: 10.1074/jbc.M111.310136. Epub 2012 Jan 20.

Biochemical inhibition of the acetyltransferases ATase1 and ATase2 reduces β-secretase (BACE1) levels and Aβ generation.

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  • 1Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.

Abstract

The cellular levels of β-site APP cleaving enzyme 1 (BACE1), the rate-limiting enzyme for the generation of the Alzheimer disease (AD) amyloid β-peptide (Aβ), are tightly regulated by two ER-based acetyl-CoA:lysine acetyltransferases, ATase1 and ATase2. Here we report that both acetyltransferases are expressed in neurons and glial cells, and are up-regulated in the brain of AD patients. We also report the identification of first and second generation compounds that inhibit ATase1/ATase2 and down-regulate the expression levels as well as activity of BACE1. The mechanism of action involves competitive and non-competitive inhibition as well as generation of unstable intermediates of the ATases that undergo degradation.

PMID:
22267734
[PubMed - indexed for MEDLINE]
PMCID:
PMC3318698
Free PMC Article

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