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

Ding Y., Ko M.H., Pehar M., Kotch F., Peters N.R., Luo Y., Salamat S.M., Puglielli L.

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.

J. Biol. Chem. 287:8424-8433(2012) [PubMed] [Europe PMC]