Effect of FSD-C10 on modulation of inflammatory microenvironment in an Alzheimer disease double transgenic mouse model / 中国病理生理杂志

ABSTRACT

AIM:To explore the therapeutic effect of a novel Rho kinase inhibitor FSD-C10 onβ-amyloid pro-tein precursor (APP)/presenilin-1 (PS1) double transgenic mice.METHODS: The transgenic mice overexpressing hu-man 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 inflammato-ry 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 deposi-tion, 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 in-flammatory microenvironment of the brain in APP/PS1 double transgenic mice .