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Fasudil inhibits the activation of microglia and astrocytes of transgenic Alzheimer's disease mice via the downregulation of TLR4/Myd88/NF-κB pathway.
J Neuroimmunol. 2020 Jun 23; 346:577284.JN

Abstract

Emerging evidence suggests an association of Alzheimer's Disease (AD) with microglial and astrocytic dysregulation. Recent studies have proposed that activated microglia can transform astrocytes to a neurotoxic A1 phenotype, which has been shown to be involved in the promotion of neuronal damage in several neurodegenerative diseases, including AD. In the present study, we observed an obvious microglial activation and A1-specific astrocyte response in the brain tissue of APP/PS1 Tg mice. Fasudil treatment improved the cognitive deficits of APP/PS1 Tg mice, inhibited microglial activation and promoted their transformation to an anti-inflammatory phenotype, and further shifted astrocytes from an A1 to an A2 phenotype. Our experiments suggest Fasudil exerted these functions by inhibing the expression of TLR4, MyD88, and NF-κB, which are key mediators of inflammation. Using in vitro experiments, we further validated in vivo findings. Our cell experiments indicated that Fasudil induces a shift of inflammatory microglia towards an anti-inflammatory phenotype. LPS-induced microglia-conditioned medium promotes A1 astrocytic polarization, but Fasudil treatment resulted in a direct transformation of A1 astrocytes to A2. To summarize, our results show that Fasudil inhibits the neurotoxic activation of microglia and shifts astrocytes towards a neuroprotective A2 phenotype, representing a promising candidate for AD treatment.

Authors+Show Affiliations

Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong 037009, China.Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong 037009, China.Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong 037009, China.Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong 037009, China.Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong 037009, China; Dept. of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan 030001, China.Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong 037009, China; Research Center of Neurobiology, The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Shanxi University of Chinese Medicine, Jinzhong 030619, China.Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong 037009, China; Dept. of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan 030001, China.Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong 037009, China.Research Center of Neurobiology, The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Shanxi University of Chinese Medicine, Jinzhong 030619, China; Dept. of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan 030001, China.Research Center of Neurobiology, The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Shanxi University of Chinese Medicine, Jinzhong 030619, China.Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong 037009, China; Dept. of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan 030001, China; Dept. of Neurology, Datong Fifth People's Hospital, Datong 037009, China. Electronic address: sxdtyjz@qq.com.Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong 037009, China; Research Center of Neurobiology, The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Shanxi University of Chinese Medicine, Jinzhong 030619, China; Dept. of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan 030001, China. Electronic address: macungen2001@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32652366

Citation

Guo, Min-Fang, et al. "Fasudil Inhibits the Activation of Microglia and Astrocytes of Transgenic Alzheimer's Disease Mice Via the Downregulation of TLR4/Myd88/NF-κB Pathway." Journal of Neuroimmunology, vol. 346, 2020, p. 577284.
Guo MF, Zhang HY, Li YH, et al. Fasudil inhibits the activation of microglia and astrocytes of transgenic Alzheimer's disease mice via the downregulation of TLR4/Myd88/NF-κB pathway. J Neuroimmunol. 2020;346:577284.
Guo, M. F., Zhang, H. Y., Li, Y. H., Gu, Q. F., Wei, W. Y., Wang, Y. Y., Zhang, X. J., Liu, X. Q., Song, L. J., Chai, Z., Yu, J. Z., & Ma, C. G. (2020). Fasudil inhibits the activation of microglia and astrocytes of transgenic Alzheimer's disease mice via the downregulation of TLR4/Myd88/NF-κB pathway. Journal of Neuroimmunology, 346, 577284. https://doi.org/10.1016/j.jneuroim.2020.577284
Guo MF, et al. Fasudil Inhibits the Activation of Microglia and Astrocytes of Transgenic Alzheimer's Disease Mice Via the Downregulation of TLR4/Myd88/NF-κB Pathway. J Neuroimmunol. 2020 Jun 23;346:577284. PubMed PMID: 32652366.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fasudil inhibits the activation of microglia and astrocytes of transgenic Alzheimer's disease mice via the downregulation of TLR4/Myd88/NF-κB pathway. AU - Guo,Min-Fang, AU - Zhang,Hui-Yu, AU - Li,Yan-Hua, AU - Gu,Qing-Fang, AU - Wei,Wen-Yue, AU - Wang,Yu-Yin, AU - Zhang,Xiao-Juan, AU - Liu,Xiao-Qin, AU - Song,Li-Juan, AU - Chai,Zhi, AU - Yu,Jie-Zhong, AU - Ma,Cun-Gen, Y1 - 2020/06/23/ PY - 2020/03/02/received PY - 2020/05/04/revised PY - 2020/05/29/accepted PY - 2020/7/12/pubmed PY - 2020/7/12/medline PY - 2020/7/12/entrez SP - 577284 EP - 577284 JF - Journal of neuroimmunology JO - J. Neuroimmunol. VL - 346 N2 - Emerging evidence suggests an association of Alzheimer's Disease (AD) with microglial and astrocytic dysregulation. Recent studies have proposed that activated microglia can transform astrocytes to a neurotoxic A1 phenotype, which has been shown to be involved in the promotion of neuronal damage in several neurodegenerative diseases, including AD. In the present study, we observed an obvious microglial activation and A1-specific astrocyte response in the brain tissue of APP/PS1 Tg mice. Fasudil treatment improved the cognitive deficits of APP/PS1 Tg mice, inhibited microglial activation and promoted their transformation to an anti-inflammatory phenotype, and further shifted astrocytes from an A1 to an A2 phenotype. Our experiments suggest Fasudil exerted these functions by inhibing the expression of TLR4, MyD88, and NF-κB, which are key mediators of inflammation. Using in vitro experiments, we further validated in vivo findings. Our cell experiments indicated that Fasudil induces a shift of inflammatory microglia towards an anti-inflammatory phenotype. LPS-induced microglia-conditioned medium promotes A1 astrocytic polarization, but Fasudil treatment resulted in a direct transformation of A1 astrocytes to A2. To summarize, our results show that Fasudil inhibits the neurotoxic activation of microglia and shifts astrocytes towards a neuroprotective A2 phenotype, representing a promising candidate for AD treatment. SN - 1872-8421 UR - https://www.unboundmedicine.com/medline/citation/32652366/Fasudil_inhibits_the_activation_of_microglia_and_astrocytes_of_transgenic_Alzheimer's_disease_mice_via_the_downregulation_of_TLR4/Myd88/NF-κB_pathway L2 - https://linkinghub.elsevier.com/retrieve/pii/S0165-5728(20)30134-X DB - PRIME DP - Unbound Medicine ER -
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