Cordycepin Improved Neuronal Synaptic Plasticity Through CREB-Induced NGF Up-Regulation Driven By Microglial M2 Polarization: A Symphony Communication Between Microglia and Neurons in AD

Abstract Background: The purpose of this study was to explore the molecular mechanism of the neuroprotective effect of Cordycepin (CCS) on improving the neuro-immune microenvironment of AD neurons by mediating microglial M2 polarization. Methods: We investigated microglial M2 polarization from M1, neuronal senescence, and synaptic plasticity by biological techniques such as animal behavior, cell biology, morphology, and bioinformatics. Results: CCS improved learning and memory impairment in 9-month-old APP/PS1 mice. CCS induced the microglial M2 polarization, up-regulated the expression and secretion level of NGF, and inhibited neuronal apoptosis, senescence, and synaptic damage caused by abnormal microglial activation in vivo and in vitro. CREB was activated by the M2 polarization and mediated the NGF expression and secretion after CCS treatment. CREB bound with the Sg3 promoter region of NGF (-1018~-1011), which increased NGF expression and secretion. CREB-induced NGF upregulation driven by microglial M2 polarization to improve the neuronal synaptic plasticity inhibits neuronal apoptosis and senescence. As a novel participant in the intercellular communication between MG and neurons, NGF contributed to the neuroprotective efficacy of CCS treatment. Conclusions: CCS improved the neuronal synaptic plasticity and senescence by promoting microglial M2 activation driven by CERB-induced NGF upregulation and conducted the symphony communication of MG-Neuron in AD.