Effect of FSD-C10 on modulation of inflammatory microenvironment in an Alzheimer disease double transgenic mouse model |
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Authors: | GU Qing-fang YU Jie-zhong WU Hao LI Yan-hua FAN Hui-jie CHAI Zhi WANG Qing XIAO Bao-guo MA Cun-gen |
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Affiliation: | 1. Institute of Brain Science, Datong University, Datong 037009, China;2. "2011" Collaborative Innovation Center/Research Center of Neurobiology, Shanxi University of Traditional Chinese Medicine, Taiyuan 030024, China;3. Institute of Neurology, Huashan Hospital, Fudan University, Shanghai 200025, China |
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Abstract: | AIM: To explore the therapeutic effect of a novel Rho kinase inhibitor FSD-C10 on β-amyloid protein precursor (APP)/presenilin-1 (PS1) double transgenic mice. METHODS: The transgenic mice overexpressing human APP with the Swedish mutation (695) and human PS1 with ΔE9 mutation at the age of 8 months were used in this study. The mice were randomly divided into model group and FSD-C10 intervention group, and wild-type mice at the same age served as normal controls. The mice in FSD-C10 intervention group were treated with FSD-C10 (25 mg·kg-1·d-1) for 2 months by intraperitoneal injection. The mice in model group and the wild-type mice were injected with saline in the similar manner. Morris water maze (MWM) test was applied to examine the capacity of learning and memory. The Aβ1-42 deposition, Tau protein phosphorylation, and the expression of β-site APP-cleaving enzyme (BACE) as well as inflammatory molecules, such as TLR-4 and NF-κB, and M1/M2 microglial markers, such as iNOS and Arg-1, were determined by the methods of immunohistochemistry and Western blot. RESULTS: Compared with model group, FSD-C10 significantly improved the learning and memory abilities of APP/PS1 double transgenic mice, accompanied by reduced Aβ1-42 deposition, Tau protein phosphorylation and BACE expression in the hippocampus. The intervention of FSD-C10 decreased the protein levels of TLR-4 and p-NF-κB, reduced the expression of iNOS and increased the expression of Arg-1 in the brain tissues. CONCLUSION: The novel Rho kinase inhibitor FSD-C10 improves the capacity of spatial learning and memory in APP/PS1 double transgenic mice, which may be related to the inhibition of TLRs/NF-κB signaling pathway, the reduction of the secretion of inflammatory molecules and the polarization of anti-inflammatory M2 microglia, thus improving the inflammatory microenvironment of the brain in APP/PS1 double transgenic mice. |
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Keywords: | APP/PS1 double transgenic mice FSD-C10 Inflammatory microenvironment TLRs/NF-κB pathway |
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