M1-Type Microglia-Derived Extracellular Vesicles Overexpressing IL-1R1 Promote Postoperative Cognitive Dysfunction by Regulating Neuronal Inflammation

Postoperative cognitive dysfunction (POCD) is a common complication after surgical anesthesia, mainly manifested as memory impairment, decreased attention, and cognitive function with mood and personality changes. Activated microglia (M1-type microglia) have been demonstrated to release inflammatory substances (IL-1β, TNF-α, etc.) that cause neuronal degeneration and death by activating the NF-κB signaling pathway and upregulating Caspase-3 and Bax. However, the pathogenesis of POCD is still not fully understood and needs further research. In the present study, we investigated the effect of M1-type microglia-derived extracellular vesicles (EVs^{M1−Microglia}) in the pathological process of POCD. The levels of NF-κB phosphorylation and IL-1β protein expression in hippocampal neurons were significantly increased in the Surgery group, while PSD95 and MAP2 were significantly decreased. Surgery induced microglia activation, synapse-associated protein decrease, and neuronal degeneration in hippocampus. And the amount of spine and mushroom spine significantly decreased in surgical mice, which was reverted in the presence of IL-1R1 siRNA. In addition, EVs^{M1−Microglia} promoted synaptic loss and neuron degeneration independent of surgery and microglia activation. Furthermore, EVs^{M1−Microglia} promoted memory defects in surgical mice. We demonstrated that EVs^{M1−Microglia} with high expression of IL-1R1 promote POCD development by regulating neuronal inflammation.