OAB-14 alleviates mitochondrial impairment through the SIRT3-dependent mechanism in APP/PS1 transgenic mice and...

Alzheimer's disease (AD) is a progressive degenerative disease that affects a growing number of elderly individuals worldwide. OAB-14, a novel chemical compound developed by our research group, has been approved by the China Food and Drug Administration (FDA) for clinical trials in patients with AD (approval no. YD-OAB-220210). Previous studies have shown that OAB-14 enhances cognitive function in APP/PS1 transgenic mice and ameliorates abnormal mitochondrial morphology in the hippocampus. Mitochondrial dysfunction is a major risk factor for the development of AD, and maintaining healthy mitochondrial morphology and function is essential for improving the pathological changes and symptoms of AD. However, the protective effects of OAB-14 on mitochondria in AD and the underlying mechanisms remain unclear. This study aimed to investigate the protective effects of OAB-14 on the mitochondria of APP/PS1 transgenic mice and N2a/APP cells. Treatment with OAB-14 restored impaired mitochondrial function, mitochondrial dynamics, mitophagy, and mitochondrial DNA (mtDNA) in APP/PS1 transgenic mice and N2a/APP cells. In APP/PS1 transgenic mice and N2a/APP cells, OAB-14-treated elevated the expression and activity of SIRT3, decreased mitochondrial acetylation, and reduced mitochondrial reactive oxygen species (mtROS) levels. OAB-14 also attenuated mitochondrial acetylation, improved mitochondrial dynamics and mitophagy, and mitigated mtDNA damage in a SIRT3-dependent manner. In addition, OAB-14 suppressed mitochondrial Aβ accumulation in the hippocampus of APP/PS1 transgenic mice. This study provides further clarification on the potential therapeutic mechanisms of OAB-14 in the treatment of AD and lays the groundwork for future drug applications.