Postoperative delirium (POD) accelerates the transition from mild cognitive impairment (MCI) to Alzheimer's disease (AD) in elderly patients. Microglial metabolic reprogramming, a pivotal aspect of the immune-inflammatory response, modulates microglia-neuron interactions and postoperative cognitive function through microenvironmental alterations. Aberrant overexpression of RUVBL2 disrupts metabolic homeostasis, leading to stress granule (SG) aggregation and fibrosis. This study investigated the role of RUVBL2 in regulating metabolic reprogramming to mediate SG formation, with the aim of identifying novel prognostic targets for inhibiting glycolysis and mitigating POD-induced MCI progression. A POD model was established in aged MCI rats using 3% sevoflurane anesthesia for 3 h, combined with open reduction and internal fixation (ORIF). Multimodal magnetic resonance imaging (MRI) was employed to assess postoperative cognitive function. Glycolytic and oxidative phosphorylation (OXPHOS) activities in primary hippocampal microglia were quantified by extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Lentiviral-mediated RUVBL2 expression modulation was performed to verify its role in microglial metabolic reprogramming. Postoperative hippocampal microglia underwent metabolic reprogramming from OXPHOS to glycolysis, with RUVBL2 expression correlating positively with POD progression. Elevated RUVBL2 expression drove metabolic reprogramming, while RUVBL2 knockdown inhibited this process, alleviated pro-inflammatory microglia-induced neuroinflammation and SG aggregation, and improved spontaneous neural activity and hippocampus-dependent cognitive deficits. In primary hippocampal microglia, RUVBL2 knockdown enhanced OXPHOS-related OCR and reduced glycolysis-associated ECAR, producing a synergistic neuroprotective effect. These findings reveal the critical role of RUVBL2 in regulating POD, highlight metabolic reprogramming as a novel therapeutic target, and suggest RUVBL2 as a promising intervention strategy for POD.
Zhang et al. (Wed,) studied this question.