作者：WU; Xian; LV; Yang-ge; TANG; Su-su; HO...tgr5neurotoxicitymemoryneuroinflammationapoptosissynapticdysfunction
摘要：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;5μL)into the mouse brain induced cognitive impairment,neuroinflammation,apoptosis,and synaptic dysfunction.In contrast,INT-777(1.5 or 3.0μg/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(synaptophysin)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.
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