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Alzheimer's disease (AD) is the most prevalent age-related disease and the most common cause of dementia in the elderly. Its hallmark neuropathological features are the presence of amyloid-beta oligomers and neurofibrillary tangles that are composed of hyperphosphorylated tau protein. SIRT1 has been shown to have a neuroprotective effect; however, its working mechanisms are not well understood. This study aimed to address this issue.We used an in vitro neuronal SH-SY5Y cell culture model to investigate the effect of SIRT1 knockdown on cell survival, proliferation, functionality, and cytotoxicity. We also investigated how SIRT1 knockdown affected relevant signaling/regulator molecules, including AKT, CREB, and p53, to gain further mechanistic insight.We found that SIRT1 knockdown inhibited cell survival, proliferation, and functionality. These effects were associated with suppressed AKT activity and CREB activation and increased p53 expression.These results will help us to better understand the protective role of SIRT1 in AD, and they support the potential use of SIRT1 as a biomarker and drug target for the prevention, diagnosis, and treatment of AD as well as other relevant age-related diseases.