|星空彩票电脑版
%A LIU Cai-hong，WU Xian，TANG Su-su，HONG Hao* %T
Involvement of TGR5 in Aβ-Induced Neurotoxicity in Vivo%0 Journal Article %D 2018 %J 神经药理学报 %R %P 11-12 %V 8 %N 4 %U {http://actanp.hebeinu.edu.cn/CN/abstract/article_534.shtml} %8 2018-08-26 %X TGR5 （Takeda G-protein-coupled receptor 5） is a bile acid G protein-coupled receptor primarily expressed in liver，gallbladder，intestine，spleen，and brain and activated by bile acids. （AD）. Herein，we evaluated the neuroprotective effects of TGR5 agonist，6α-ethyl-23（S）-methylcholic acid （S-EMCA，INT-777），in the Aβ1-42-treated mouse model of acute neurotoxicity. Single intracerebroventricular（ i.c.v.） injection of aggregated Aβ1-42（ 410 pmol/mouse；5 μL） into the mouse brain induced cognitive impairment，neuroinflammation，apoptosis，and synaptic dysfunction. In contrast，INT-777 （1.5 or 3.0 μg/mouse，i.c.v.） significantly improved Aβ1-42-induced cognitive impairment，as reflected by better performance in memory tests. Importantly， INT-777 treatment reversed Aβ1-42-induced TGR5 down-regulation，suppressed the increase of nuclear NF-κB p65，and mitigated neuroinflammation，as evidenced by lower proinflammatory cytokines and less Iba1-positive cells in the hippocampus and frontal cortex. INT-777 treatment
also pronouncedly suppressed apoptosis through the reduction of TUNEL-positive cells， decreased activation of caspase-3，increased the ratio of Bcl-2/Bax，and ameliorated synaptic dysfunction by promoting dendritic spine generation with the upregulation of postsynaptic （PSD95） and presynaptic proteins in Aβ1-42-treated mice. Our results indicate that INT-777 has potent neuroprotective effects against Aβ1-42-induced neurotoxicity. Taken together，these findings suggest that TGR5 might participate in the pathogenesis of Alzheimer’s disease.