Metabolic Stress Modulates Alzheimer’s β-Secretase Gene Transcription via SIRT1-PPARγ-PGC-1 in Neurons

• Published in: Cell metabolism Vol. 17; no. 5; pp. 685 - 694
• Main Authors: Wang, Ruishan, Li, Jing Jing, Diao, Shiyong, Kwak, Young-Don, Liu, Li, Zhi, Lianteng, Büeler, Hansruedi, Bhat, Narayan R., Williams, Robert W., Park, Edwards A., Liao, Francesca-Fang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.05.2013
• Subjects: Acetylation; Alzheimer Disease - enzymology; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Amyloid Precursor Protein Secretases - biosynthesis; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Animals; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - metabolism; Down-Regulation; Mice; Mice, Inbred C57BL; Neurons - metabolism; Nitric Oxide Synthase Type III - deficiency; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR gamma - genetics; PPAR gamma - metabolism; Promoter Regions, Genetic; Rats; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Stress, Physiological - genetics; Stress, Physiological - physiology; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Up-Regulation
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2013.03.016

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. [Display omitted] •High-fat diets or eNOS deficiency upregulated BACE1 transcription in mice•Fasting suppressed BACE1 through SIRT1-mediated deacetylation of PPARγ- PGC-1•Up- or downregulation of PGC-1α reciprocally regulated BACE1 in vitro and in vivo•SIRT1-PPARγ- PGC-1 suppression of BACE may slow progression of Alzheimer’s disease