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

•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

SummaryClassic 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.

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