To investigate whether silent mating-type information regulation 2 homolog 1 (SIRT1) plays a neuroprotective role in connection with Alzheimer's 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 (AβO) were used. The animals were treated with resveratrol (RSV) or suramin for two months; and cell cultures with RSV, suramin, the PGC-1α stimulator ZLN005 and transient transfection with PGC-1α RNA silence. The level of SIRT1 in brain tissues from patients with AD and APP/PS1 mice, as well as in primary neurons exposed to AβO was decreased, including SIRT1 proteins in nuclear or mitochondria. Over-expression of APP/PS1 was demonstrated to exhibit impaired learning and memory of mice; more senile plaques, disrupted membranes and broken or absent cristae of mitochondria in the brain; the decreased levels of ADAM10, BACE2, OGG1, PGC-1α, and NAD+, while the increased levels of BACE1 and apoptosis. Interestingly, these changes were attenuated significantly by treatment with RSV, but enhanced by suramin. By activating PGC-1α but inhibiting SIRT1, the extent of apoptotic death in cells were significantly declined; however, by activating SIRT1 but inhibiting PGC-1α with siPGC-1α, these levels remained unchanged. These findings indicate that SIRT1 may protect against the neurotoxicity associated with AD, which in mechanism might involve the regulation of PGC-1α.