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

• DOI: 10.1016/j.cmet.2013.03.016
• Publication Date: 2013-05-07T18:58:46Z
• Authors: Ruishan Wang; Jing Jing Li; Shiyong Diao; Young-Don Kwak; Li Liu; Lianteng Zhi; Hansruedi Büeler; Narayan R. Bhat; Robert W. Williams; Edwards A. Park; Francesca-Fang Liao
• Keywords: Neurons; 0303 health sciences; Nitric Oxide Synthase Type III; Transcription, Genetic; Physiology; Down-Regulation; Acetylation; Cell Biology; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Up-Regulation; Mice, Inbred C57BL; PPAR gamma; Mice; 03 medical and health sciences; Sirtuin 1; Alzheimer Disease; Stress, Physiological; Animals; Aspartic Acid Endopeptidases; Amyloid Precursor Protein Secretases; Promoter Regions, Genetic; Molecular Biology; Transcription Factors

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.