9-Methylfascaplysin Prevents Neuroinflammation and Synaptic Damage via Cell-Specific Inhibition of Kinases in APP/PS1 Transgenic Mice.

Autor: Le J; Translational Medicine Center of Pain, Emotion and Cognition, Health Science Center, Ningbo University, Zhejiang, China., Xia C; Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Ningbo University, Zhejiang, China., Xu J; Translational Medicine Center of Pain, Emotion and Cognition, Health Science Center, Ningbo University, Zhejiang, China., Cai J; Translational Medicine Center of Pain, Emotion and Cognition, Health Science Center, Ningbo University, Zhejiang, China., Hu C; Translational Medicine Center of Pain, Emotion and Cognition, Health Science Center, Ningbo University, Zhejiang, China., Bai Y; College of Food and Pharmaceutical Sciences, Ningbo University, Zhejiang, China., Chen H; Translational Medicine Center of Pain, Emotion and Cognition, Health Science Center, Ningbo University, Zhejiang, China., Rong W; Translational Medicine Center of Pain, Emotion and Cognition, Health Science Center, Ningbo University, Zhejiang, China., Jiang Y; Translational Medicine Center of Pain, Emotion and Cognition, Health Science Center, Ningbo University, Zhejiang, China., Wu X; College of Biotechnology, Tianjin University of Science & Technology; Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, Tianjin, China., Li Y; School Infirmary, Ningbo University, Zhejiang, China., Wang Q; Translational Medicine Center of Pain, Emotion and Cognition, Health Science Center, Ningbo University, Zhejiang, China., Naman CB; Department of Science and Conservation, San Diego Botanic Garden, California, USA., Wei H; Ningbo College of Health Sciences, Zhejiang, China., Zhang J; Translational Medicine Center of Pain, Emotion and Cognition, Health Science Center, Ningbo University, Zhejiang, China., Liu H; Translational Medicine Center of Pain, Emotion and Cognition, Health Science Center, Ningbo University, Zhejiang, China., Chen X; Translational Medicine Center of Pain, Emotion and Cognition, Health Science Center, Ningbo University, Zhejiang, China., Liu F; College of Biotechnology, Tianjin University of Science & Technology; Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, Tianjin, China., Liang H; Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Ningbo University, Zhejiang, China., Cui W; Translational Medicine Center of Pain, Emotion and Cognition, Health Science Center, Ningbo University, Zhejiang, China.; Ningbo Kangning Hospital, Ningbo University, Zhejiang, China.; The First Affiliated Hospital of Ningbo University, Zhejiang, China.
Jazyk: angličtina
Zdroj: CNS neuroscience & therapeutics [CNS Neurosci Ther] 2024 Nov; Vol. 30 (11), pp. e70100.
DOI: 10.1111/cns.70100
Abstrakt: 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.
(© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje