Dexmedetomidine mitigates postoperative delirium in aged mice via TFEB-linked restoration of microglial lysosomal function and attenuated neuroinflammation

BACKGROUND: Postoperative delirium (POD) is a serious complication in elderly patients. Dexmedetomidine (DEX) can reduce POD incidence, but its neuroprotective mechanisms are unclear. This study investigated whether DEX alleviates POD-like phenotypes and whether hippocampal transcription factor EB (TFEB) contributes to this effect, with a focus on microglial lysosomal function. METHODS: An aged mouse POD model was established via laparotomy with visceral manipulation. Mice were assigned to Sham, POD, and POD+DEX groups. Behavioral tests assessed cognitive and affective functions. Hippocampal tissues were analyzed for neuroinflammation and lysosomal markers. Primary microglia were isolated for in vitro studies involving TFEB knockdown. RESULTS: DEX treatment significantly ameliorated POD-like behaviors and reduced hippocampal microglial activation and pro-inflammatory cytokine levels. DEX treatment was associated with increased lysosomal protein expression and promoted TFEB nuclear translocation in microglia, correlating with enhanced lysosomal gene transcription. In vitro, DEX increased lysosomal acidity and improved functional readouts in LPS-stimulated microglia in a TFEB-dependent manner, suggesting partial recovery of lysosome-dependent clearance. DEX also inhibited the NLRP3 inflammasome pathway, an effect substantially attenuated by TFEB knockdown. Mechanistically, DEX-mediated TFEB activation was associated with reduced mTOR activity. CONCLUSION: DEX mitigates POD-like phenotypes in aged mice, with evidence that TFEB activation in the hippocampus contributes to restoration of lysosomal function and attenuation of neuroinflammation. Microglia appear to be a key cellular compartment in this process. These findings suggest that enhancing lysosomal function may represent a potential target for POD.