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

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 beta-secretase/BACE1, the rate-limiting enzyme for A beta generation, in eNOS-deficient mouse brains and after feeding mice a high-fat, high-cholesterol diet. Up-or down-regulation of PGC-1 alpha 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 PPAR gamma, likely via SIRT1-mediated deacetylation in a ligand-independent manner. The BACE1 promoter contains multiple PPAR-RXR sites, and direct interactions among SIRT1-PPAR gamma-PGC-1 at these sites were enhanced with fasting. The interference on the BACE1 gene identified here represents a unique noncanonical mechanism of PPAR gamma-PGC-1 in transcriptional repression in neurons in response to metabolic signals that may involve recruitment of corepressor NCoR.