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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetyltransferases / antagonists & inhibitors
  • Acetyltransferases / genetics
  • Acetyltransferases / metabolism*
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / biosynthesis*
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases / biosynthesis*
  • Aspartic Acid Endopeptidases / genetics
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Mice
  • Mice, Transgenic
  • Neuroglia / metabolism*
  • Neuroglia / pathology
  • Neurons / metabolism*
  • Neurons / pathology
  • PC12 Cells
  • Rats
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Acetyltransferases
  • NAT8 protein, human
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse
  • Bace1 protein, rat