Silent Mating–Type Information Regulation 2 Homolog 1 Attenuates the Neurotoxicity Associated with Alzheimer Disease via a Mechanism Which May Involve Regulation of Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-α

To investigate the neuroprotective role of silent mating-type information regulation 2 homolog 1 (SIRT1) in Alzheimer disease (AD), brain tissues from patients with AD and APP/PS1 mice as well as primary rat neurons exposed to oligomers of amyloid-β peptide were examined. The animals were treated with resveratrol (RSV) or suramin for 2 months. Cell cultures were treated with RSV, suramin, and the peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) stimulator ZLN005. Cells were transiently transfected with PGC-1α silencing RNA. The level of SIRT1 in brain tissues from patients with AD and APP/PS1 mice, including nuclear and mitochondrial proteins, as well as in primary neurons exposed to oligomers of amyloid-β peptide, was decreased. Overexpression of APP/PS1 impaired learning and memory of mice; produced more senile plaques, disrupted membranes, and resulted in broken or absent cristae of mitochondria in the brain; decreased levels of A disintegrin and metallopeptidase domain 10, beta-secretase 2, 8-oxoguanine DNA glycosylase-1, PGC-1α, and NAD+; and increased levels of beta-secretase 1 and apoptosis. Interestingly, these changes were attenuated significantly by RSV treatment but enhanced by suramin administration. By activating PGC-1α but inhibiting SIRT1, apoptotic cell death was significantly decreased; however, by activating SIRT1 but inhibiting PGC-1α with small interfering PGC-1α, these levels remained unchanged. These findings indicate that SIRT1 may protect against AD-associated neurotoxicity, which might involve PGC-1α regulation.