title: Biochemical inhibition of the acetyltransferases ATase1 and ATase2 reduces β-secretase (BACE1) levels and Aβ generation.
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.
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ding
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Ko
authors.forename: Mariana
authors.initials: M
authors.lastname: Pehar
authors.forename: Frank
authors.initials: F
authors.lastname: Kotch
authors.forename: Noel R
authors.initials: NR
authors.lastname: Peters
authors.forename: Yun
authors.initials: Y
authors.lastname: Luo
authors.forename: Shahriar M
authors.initials: SM
authors.lastname: Salamat
authors.forename: Luigi
authors.initials: L
authors.lastname: Puglielli
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016716:PC12 Cells; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D000123:Acetyltransferases; C116373:NAT8 protein, human; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; C509281:Bace1 protein, rat