Abstract
Classic cardio-metabolic risk factors such as hypertension, stroke, diabetes, and hypercholesterolemia all increase the risk of Alzheimer's disease. We found increased transcription of β-secretase/BACE1, the rate-limiting enzyme for Aβ generation, in eNOS-deficient mouse brains and after feeding mice a high-fat, high-cholesterol diet. Up- or downregulation of PGC-1α reciprocally regulated BACE1 in vitro and in vivo. Modest fasting in mice reduced BACE1 transcription in the brains, which was accompanied by elevated PGC-1 expression and activity. Moreover, the suppressive effect of PGC-1 was dependent on activated PPARγ, likely via SIRT1-mediated deacetylation in a ligand-independent manner. The BACE1 promoter contains multiple PPAR-RXR sites, and direct interactions among SIRT1-PPARγ-PGC-1 at these sites were enhanced with fasting. The interference on the BACE1 gene identified here represents a unique noncanonical mechanism of PPARγ-PGC-1 in transcriptional repression in neurons in response to metabolic signals that may involve recruitment of corepressor NCoR.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Alzheimer Disease / enzymology
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Alzheimer Disease / genetics*
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Alzheimer Disease / metabolism
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Alzheimer Disease / physiopathology
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Amyloid Precursor Protein Secretases / biosynthesis
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Amyloid Precursor Protein Secretases / genetics*
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Amyloid Precursor Protein Secretases / metabolism
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Animals
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Aspartic Acid Endopeptidases / genetics
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Aspartic Acid Endopeptidases / metabolism
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Down-Regulation
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Mice
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Mice, Inbred C57BL
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Neurons / metabolism*
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Nitric Oxide Synthase Type III / deficiency
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Nitric Oxide Synthase Type III / genetics
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Nitric Oxide Synthase Type III / metabolism
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PPAR gamma / genetics*
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PPAR gamma / metabolism
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Promoter Regions, Genetic
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Rats
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Sirtuin 1 / genetics*
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Sirtuin 1 / metabolism
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Stress, Physiological / genetics
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Stress, Physiological / physiology*
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Transcription, Genetic
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Up-Regulation
Substances
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PPAR gamma
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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Transcription Factors
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Nitric Oxide Synthase Type III
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Nos3 protein, mouse
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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Bace1 protein, mouse
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Sirt1 protein, mouse
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Sirtuin 1