2. Academic Validation
  3. Cordycepin improved neuronal synaptic plasticity through CREB-induced NGF upregulation driven by MG-M2 polarization: a microglia-neuron symphony in AD

Cordycepin improved neuronal synaptic plasticity through CREB-induced NGF upregulation driven by MG-M2 polarization: a microglia-neuron symphony in AD

  • Biomed Pharmacother. 2022 Nov 30;157:114054. doi: 10.1016/j.biopha.2022.114054.
Linchi Jiao 1,  Zhihua Yu 2,  Xin Zhong 3,  Weifan Yao 4,  Lijuan Xing 5,  Guowei Ma 6,  Jiajia Shen 7,  Yuqiang Wu 8,  Ke Du 9,  Junxiu Liu 10,  Junhui Tong 11,  Jia Fu 12,  Minjie Wei 13,  Mingyan Liu 14
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China. Electronic address: lcjiao@cmu.edu.cn.
  • 2 Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China. Electronic address: cmuyuzh@163.com.
  • 3 Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China. Electronic address: xzhong@cmu.edu.cn.
  • 4 Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China. Electronic address: ywf3209@163.com.
  • 5 Precision Laboratory of Panjin Central Hospital, Panjin, 124000, China. Electronic address: xinglijuan1972@163.com.
  • 6 Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China. Electronic address: 1182157068@qq.com.
  • 7 Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China. Electronic address: 17704208059@163.com.
  • 8 Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China. Electronic address: 1362978990@qq.com.
  • 9 Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China. Electronic address: 125653224@qq.com.
  • 10 Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China. Electronic address: 1539139085@qq.com.
  • 11 Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China. Electronic address: 1348332083@qq.com.
  • 12 Liaoning Medical Diagnosis and Treatment Center, Shenyang, 110179, China. Electronic address: 1522403422@qq.com.
  • 13 Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China; Liaoning Medical Diagnosis and Treatment Center, Shenyang, 110179, China. Electronic address: minjie_wei@163.com.
  • 14 Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China. Electronic address: saffer@163.com.
PMID: 36462314 DOI: 10.1016/j.biopha.2022.114054
Abstract

Purpose: Microglia-neuron crosstalk is critically involved in synaptic plasticity and degeneration by releasing diverse mediators in Alzheimer's disease (AD). Therefore, determining contributors that modulate the systemic microenvironment is essential. Cordycepin (CCS) is a novel neuroprotective compound obtained from Cordyceps militaris. However, the anti-AD efficacy and potential mechanism of CCS treatment remain unclear. This study aimed to elucidate the microglia-neuron symphony in AD after CCS treatment and to explore the possible mechanisms of its neuroprotective efficacy.

Methods and results: CCS treatment improved learning and memory impairment in 9-month-old APP/PS1 mice by behavioral tests. CCS polarized the microglia from M1 to M2, inhibited neuronal Apoptosis and promoted synaptic remodeling accompanied by in vivo and in vitro upregulation of NGF. The cAMP-response element-binding protein (CREB) was also activated after MG-M2 polarization. Further, we verified that the sg3 promoter region of NGF (-1018 to -1011) is the key binding site for CREB-induced NGF transcription, which increased NGF expression and secretion. Finally, microglia-derived NGF was confirmed as an important mediator in microglia-neuron symphony to improve the neuronal microenvironment after CCS treatment.

Conclusions: CCS improved the neuronal synaptic plasticity and senescence by promoting MG-M2 activation driven by CREB-induced NGF upregulation and facilitated symphony communication between the microglia and neuron in AD. This study provides a new perspective on the development of a novel strategy for anti-AD therapy and offers new targets for anti-AD drug development.

Keywords

Alzheimer’s disease; CREB; Cordycepin; Microglial M2 polarization; NGF.

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