title: Metabolic stress modulates Alzheimer's β-secretase gene transcription via SIRT1-PPARγ-PGC-1 in neurons.
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.
authors.affiliation: Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, 874 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Ruishan
authors.initials: R
authors.lastname: Wang
authors.forename: Jing Jing
authors.initials: JJ
authors.lastname: Li
authors.forename: Shiyong
authors.initials: S
authors.lastname: Diao
authors.forename: Young-Don
authors.initials: YD
authors.lastname: Kwak
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Lianteng
authors.initials: L
authors.lastname: Zhi
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Büeler
authors.forename: Narayan R
authors.initials: NR
authors.lastname: Bhat
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
authors.forename: Edwards A
authors.initials: EA
authors.lastname: Park
authors.forename: Francesca-Fang
authors.initials: FF
authors.lastname: Liao
mesh_terms: D000107:Acetylation; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D051381:Rats; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1