Biochemical Inhibition of the Acetyltransferases ATase1 and ATase2 Reduces β-Secretase (BACE1) Levels and Aβ Generation

• Published in: The Journal of biological chemistry 2012-03, Vol.287 (11), p.8424-8433
• Main Authors: Ding, Yun, Ko, Mi Hee, Pehar, Mariana, Kotch, Frank, Peters, Noel R., Luo, Yun, Salamat, Shahriar M., Puglielli, Luigi
• Format: Article
• Language: English
• Subjects: Acetyl Coenzyme A; Acetyltransferases - antagonists & inhibitors; Acetyltransferases - genetics; Acetyltransferases - metabolism; Alzheimer Disease; Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein; Amyloid Precursor Protein Secretases - biosynthesis; Amyloid Precursor Protein Secretases - genetics; Animals; Aspartic Acid Endopeptidases - biosynthesis; Aspartic Acid Endopeptidases - genetics; BACE1; CHO Cells; Cricetinae; Cricetulus; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Enzymologic; Humans; Lysine Acetylation; Mice; Mice, Transgenic; Neurobiology; Neurodegenerative Diseases; Neuroglia - metabolism; Neuroglia - pathology; Neurons - metabolism; Neurons - pathology; Neuroscience; PC12 Cells; Rats; Up-Regulation - drug effects; Up-Regulation - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.310136

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. The acetyltransferases ATase1 and ATase2 regulate the levels of BACE1, which is involved in the pathogenesis of Alzheimer disease (AD). Both ATases are up-regulated in the brain of AD patients. ATase1/ATase2 inhibitors were identified. Structure-activity relationship, mechanisms of action, and biological effects were determined. ATase1/ATase2 inhibitors down-regulate levels and activity of BACE1. ATase1/ATase2 are potential targets to prevent AD.