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CNS Neuroscience & Therapeutics

CNS Neuroscience & Therapeutics

IF: 4.79
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9‐Methylfascaplysin Prevents Neuroinflammation and Synaptic Damage via Cell‐Specific Inhibition of Kinases in?APP/PS1 Transgenic Mice

Published:19 November 2024 DOI: 10.1111/cns.70100
Jingyang Le, Chenglong Xia, Jiayi Xu, Jinhan Cai, Chenwei Hu, Yu Bai, Huiyue Chen, Wenni Rong, Yujie Jiang, Xinming Wu, Yongmei Li, Qiyao Wang, C. Benjamin Naman, Hua Wei, Jili Zhang, Hao Liu, Xiaowei Chen, Fufeng Liu, Hongze Liang, Wei Cui

Abstract

Background

Alzheimer's disease (AD) is a leading neurodegenerative disorder without effective treatments. The nonlinear dynamic nature of AD pathophysiology suggested that multiple pharmacological actions of anti-AD drugs should be elucidated. 9-Methylfascaplysin (9-MF) was previously designed and synthesized as a novel anti-AD candidate.

Methods and Results

In this study, 9-MF at low concentrations significantly prevented cognitive impairments with similar efficacy as donepezil in APP/PS1 transgenic mice. In addition, 9-MF potently reduced β-amyloid (Aβ)-associated neuroinflammation and tau-associated synaptic damage in?vivo. 9-MF-regulated microglia-specific differentially phosphorylated proteins (DPPs) were mainly enriched in neuroinflammation, while 9-MF-regulated neuron-specific DPPs were enriched in synaptic regulation, as revealed by a quantitative phosphoproteomic approach. A phosphoproteome-kinome algorithm further identified that rho-associated coiled-coil kinase 2 (ROCK2) and glycogen synthase kinase 3β (GSK3β) ranked high in 9-MF-downregulated kinase perturbations. 9-MF possessed high affinities for ROCK2 and GSK3β, which was confirmed by in?vitro kinase activity assay. The protective effects of 9-MF were abolished by ROCK2 knockdown in Aβ-treated BV2 microglial cells, and by GSK3β knockdown in glyceraldehyde-treated SH-SY5Y neuronal cells, respectively.

Conclusions

All these results supported that 9-MF produced anti-AD effects via cell-specific inhibition of ROCK2 and GSK3β in microglia and neurons, respectively.

Substances (2)

Materials
Procduct Name CAS Molecular Formula Supplier Price
1,1,1,3,3,3-Hexafluoro-2-propanol 920-66-1 C3H2F6O 700 suppliers $6.00-$6556.24
4',6-Diamidino-2-phenylindole dihydrochloride 28718-90-3 C16H16ClN5 296 suppliers $14.10-$4800.00

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