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) 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 promoted synaptic loss and neuron degeneration independent of surgery and microglia activation. Furthermore, EVs promoted memory defects in surgical mice. We demonstrated that EVs with high expression of IL-1R1 promote POCD development by regulating neuronal inflammation.