神经药理学报 ›› 2018, Vol. 8 ›› Issue (4): 53-54.
• Session 3A: Cognition in Alzheimer’s Disease: Animal Models and Intracellular Mechanisms • 上一篇 下一篇
WU Xian, LV Yang-ge, TANG Su-Su, HONG Hao
WU Xian, LV Yang-ge, TANG Su-Su, HONG Hao
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; 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 (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.
