Cordycepin improved neuronal synaptic plasticity through CREB-induced NGF upregulation driven by MG-M2 polarization: a microglia-neuron symphony in AD - 08/12/22
, Zhihua Yu a, 1 , Xin Zhong a , Weifan Yao a , Lijuan Xing c , Guowei Ma a , Jiajia Shen a , Yuqiang Wu a , Ke Du a , Junxiu Liu a , Junhui Tong a , Jia Fu b , Minjie Wei a, b, ⁎ , Mingyan Liu a, ⁎ 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.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | CCS improves neuronal function via inducing microglial M2 polarization. |
• | MG-derived NGF is the key mediator for MG-neuron symphony after CCS treatment. |
• | CCS increases MG-derived NGF level by CREB activation. |
• | Sg3 (–1018 to –1011) is the key binding site for CREB-induced NGF transcription. |
Abbreviations : AD, CCS, NGF, CREB, MG, CNS, Aβ, EGCG, LPS, IFNγ, APP, PS, β-Gal, MAP2, NeuN, GAP43, Syn, PSD 95, TNF-α, Arg1, IL-1β, iNOS, IL-10, TGF-β, Iba-1
Keywords : Cordycepin, Microglial M2 polarization, CREB, NGF, Alzheimer’s disease
Plan
Vol 157
Article 114054- janvier 2023 Retour au numéro
Article précédent
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