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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acetyltransferases / antagonists & inhibitors
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Acetyltransferases / genetics
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Acetyltransferases / metabolism*
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Alzheimer Disease / drug therapy
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism*
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Alzheimer Disease / pathology
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Amyloid Precursor Protein Secretases / biosynthesis*
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Amyloid Precursor Protein Secretases / genetics
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism*
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Animals
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Aspartic Acid Endopeptidases / biosynthesis*
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Aspartic Acid Endopeptidases / genetics
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CHO Cells
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Cricetinae
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Cricetulus
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Enzymologic*
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Humans
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Mice
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Mice, Transgenic
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Neuroglia / metabolism*
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Neuroglia / pathology
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Neurons / metabolism*
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Neurons / pathology
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PC12 Cells
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Rats
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Up-Regulation / drug effects
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Up-Regulation / genetics
Substances
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Amyloid beta-Peptides
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Enzyme Inhibitors
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Acetyltransferases
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NAT8 protein, human
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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Bace1 protein, mouse
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Bace1 protein, rat