Propofol induces mitochondrial dysfunction in hippocampal neurons and postoperative cognitive dysfunction in male 3xTg-AD mice by blocking ESRRG-mediated HSD11B2 transcription

Cognitive dysfunction is a severe issue of Alzheimer's disease (AD). This study explores the molecular mechanisms underlying propofol-induced postoperative cognitive dysfunction (POCD) in AD mice. Triple transgenic AD (3xTg-AD) male mice or control C57BL/6J mice were subjected to propofol anesthesia and abdominal surgery for modeling. AAV-mediated gene intervention was performed on male 3xTg-AD mice prior to propofol anesthesia. Reduced estrogen-related receptor gamma (ESRRG) and hydroxysteroid 11-beta dehydrogenase 2 (HSD11B2) expression was found in the hippocampus of male 3xTg-AD mice. ESRRG overexpression mitigated POCD and hippocampal mitochondrial dysfunction in male 3xTg-AD mice exposed to propofol. This was evidenced by shorter escape latencies, longer target quadrant times, increased platform crossings, reduced malondialdehyde and mitochondrial Reactive Oxygen Species, decreased cytosolic cytochrome C and phosphorylated dynamin-related protein 1 (p-DRP1), and higher mitochondrial membrane potential, though these effects were reversed by HSD11B2 knockdown. In vitro, propofol lowered HT22 cell mitochondrial membrane potential and elevated cytochrome C and p-DRP1, but ESRRG overexpression countered these changes. Ultimately, propofol disrupts ESRRG-mediated HSD11B2 transcription, driving mitochondrial dysfunction and POCD in male 3xTg-AD mice.