SIRT4 promotes neuronal apoptosis in models of Alzheimer's disease via the STAT2-SIRT4-mTOR pathway

Alzheimer's disease (AD) is the leading cause of dementia and presents a considerable disease burden. Its pathology involves substantial neuronal loss, primarily attributed to neuronal Apoptosis. Although Sirtuin 4 (SIRT4) has been implicated in regulating Apoptosis in various diseases, the role of SIRT4 in AD pathology remains unclear. The study employed APP/PS1 mice as an animal model of AD and Amyloid-β (Aβ)1-42-treated HT-22 cells as an AD cell model. SIRT4 expression was determined by quantitative real-time polymerase chain reaction, western blot, and immunofluorescence. A Sirt4 knockdown model was established by intracranial injection of lentivirus-packaged sh-SIRT4 and cellular lentivirus transfection. Immunohistochemistry and flow cytometry were used to examine Aβ deposition in mice and Apoptosis, respectively. Protein expression was assessed by western blot analysis. The UCSC and JASPAR databases were used to predict upstream transcription factors of SIRT4. Subsequently, the binding of transcription factors to SIRT4 was analyzed using a dual-luciferase assay and chromatin immunoprecipitation. SIRT4 expression was upregulated in both APP/PS1 mice and Aβ-treated HT-22 cells in comparison to their respective control groups. Sirt4 knockdown in animal and cellular models of AD resulted in reduced Apoptosis, decreased Aβ deposition, and amelioration of learning and memory impairments in mice. Mechanistically, SIRT4 modulates Apoptosis via the mTOR pathway and is negatively regulated by the transcription factor signal transducer and activator of transcription 2 (STAT2). Our study findings suggest that targeting the STAT2-SIRT4-mTOR axis may offer a new treatment approach for AD.

Alzheimer's disease; Apoptosis; Sirtuin 4; Transcription factor STAT2; mTOR.