Qifuyin against CCL11-Induced cognitive impairment by inhibiting microglial senescence via CCR3 signaling.

Abstract

Background: The chemokine CCL11 is negatively correlated with cognitive function and is able to cause dysfunctions of synaptic plasticity. This research investigate whether CCL11 induce microglia senescence to damage synaptic plasticity and the protective role of Qifuyin.

Method: This study involved the intraperitoneal injection of CCL11 in C57BL/6 mice to create an ageing mouse model. Behavioral tests were conducted to evaluate the changes in cognitive function after Qifuyin treatment. LTP and Golgi staining were used to evaluate synaptic structure and function. Cellular senescence was assessed using SA-β-Gal staining, co-localization of p21 or p16 with Iba-1 was identified using multiplex immunofluorescence, and senescence-associated secretory phenotype (SASP) was evaluated via the Luminex. CCR3 knockout/overexpression HMC3 cells were treated with five brain-entering components of Qifuyin to observe protective effects of Qifuyin.

Results: Here we found that Qifuyin improved the ability of object recognition and memory, spatial learning and memory and conditional fear memory in CCL11-induced cognitive dysfunction of C57BL/6 mice. Qifuyin can improve synaptic plasticity, increase the expression of GAP-43, PSD-95 and SYN in the hippocampus of CCL11-induced mice. Cellular senescence of microglia and the amounts of SASP in the hippocampus were also reduced after Qifuyin treatment. Through the study of HMC3 cells with CCR3 gene knockout/overexpression, it was found that the brain components of Qifuyin could unlock the cell cycle arrest induced by CCL11/CCR3 pathway, reduce the proportion of G0 and G1 cells, reduce the expressions of p16, p21 and SASP, and enhance the synaptic connection of HT-22 cells damaged by HMC3 cells.

Conclusion: This study discovered that CCL11 precipitates microglia senescence in brain, resulting in synaptic structural damage and impaired neuronal functional plasticity, hence causing disruptions in learning and memory functions. Qifuyin can mitigate microglial senescence, safeguard synaptic plasticity, and enhance cognitive function.