The Role of Sirt1 in Regulating Inflammatory Cytokines and Oxidative Stress in the Transition Mechanism from Depressive Disorder to Alzheimer's Disease.

This study aimed to investigate the role of Sirt1 in the transition from depressive disorder (DD) to Alzheimer's disease (AD), focusing on the regulation of inflammatory factors and oxidative stress through modulation of acetylation substrates. Male C57BL/6 and APP/PS1 mice were used to establish a mouse model of chronic unpredictable mild stress (CUMS). Depressive and anxiety behaviors, as well as cognitive function, were evaluated in model mice. A range of techniques, including immunohistochemistry, qRT-PCR, western blotting, and ELISA, was used to investigate the performance of the model mice. VENN analysis was used to identify hub genes and signaling pathways regulated by Sirt1. Finally, differential expression analysis between the AD + DD and DD groups was conducted using transcriptome sequencing, and data processing was conducted using DESeq2 software. Behavioral experiments revealed that, following CUMS stimulation, both APP/PS1 and C57BL/6 mice exhibited significantly reduced responsiveness, anhedonia, depression, despair, and impaired spatial exploration abilities. Performance analysis further demonstrated that CUMS treatment activated microglial cells, suppressed both the mRNA and protein expression of Sirt1, and promoted the expression of GM-CSF, IL-6, TNF-α, NO, MDA, and ROS. In addition, CUMS exposure inhibited the expression of SOD. Bioinformatic analysis and transcriptome sequencing of the Sirt1 receptor indicated that Sirt1 regulates the RelA/NLRP3 signaling pathway, which might subsequently affect the expression and function of differentially expressed genes, thereby promoting the transition from DD to AD. CUMS stimulation induced depressive and anxious behaviors, cognitive impairments, activation of microglial cells, reduced expression of Sirt1, and increased levels of inflammatory factors and oxidative stress markers in AD mice. Bioinformatic analysis and transcriptome sequencing suggested that Sirt1 may influence the expression and function of differentially expressed genes by regulating the RelA/NLRP3 signaling pathway, thereby promoting the transition from DD to AD.