Dexmedetomidine attenuates Alzheimer’s pathogenesis by targeting the ROS-mediated XIAP-MDM2-p53 signaling axis

Introduction Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder with a complex pathological process, in which oxidative stress serves as a key pathogenic mechanism. Studies have shown that the anesthetic adjuvant dexmedetomidine (Dex) can improve postoperative cognitive function in AD patients. This study aimed to explore whether dexmedetomidine alleviates AD-associated neuronal apoptosis and cognitive impairment via reducing overproduction of ROS and regulating the XIAP signaling pathway. Methods In vitro experiments were conducted using Aβ1-42-exposed SH-SY5Y cells and primary neurons, employing interventions such as the ROS scavenger NAC, yohimbine pre-treatment, and siRNA-mediated XIAP knockdown. In vivo cognitive deficits and brain pathology were evaluated in AD model mice using Morris water maze tests and immunofluorescence staining. Results Experimental results demonstrated that Aβ1-42 induced apoptosis in neuronal cells, while dexmedetomidine incubation significantly reduced Aβ1-42 elicited ROS generation, activated XIAP, suppressed MDM2 and ameliorated P53 overactivation, thereby effectively preventing neuronal death. Combined administration of NAC and dexmedetomidine reversed Aβ1-42-induced XIAP inhibition, ROS accumulation, and cell apoptosis. Furthermore, both yohimbine pre-treatment and XIAP knockdown effectively abrogated the ability of Dex to reduce ROS accumulation and mitigate apoptosis. In vivo results indicated that dexmedetomidine improved cognitive deficits and intervened in AD pathology in the hippocampal region of AD model mice. Conclusion This study reveals that dexmedetomidine inhibits ROS release and activates the XIAP-MDM2-p53 signaling pathway, thereby delaying apoptosis and ameliorating cognitive impairment in AD progression.