Neuroprotective effects of INT-777 against Aβ1–42-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice.

Highlights • INT-777 ameliorates cognitive impairment induced by intracerebroventricular injection of Aβ 1–42 in mice. • INT-777 attenuates Aβ 1–42 -induced neuroinflammation, apoptosis, and synaptic dysfunction in mice. • INT-777 reverses Aβ 1–42 -induced TGR5 down-regulation in the hippocampus and frontal cortex. Abstract Increasing evidence demonstrates that the neurotoxicity of amyloid-beta (Aβ) deposition plays a causative role in Alzheimer’s disease (AD). Herein, we evaluated the neuroprotective effects of 6α-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777), a specific G-protein coupled bile acid receptor 1 (TGR5) agonist, in the Aβ 1–42 -treated mouse model of acute neurotoxicity. Single intracerebroventricular (i.c.v.) injection of aggregated Aβ 1–42 (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 Aβ 1–42 -induced cognitive impairment, as reflected by better performance in memory tests. Importantly, INT-777 treatment reversed Aβ 1–42 -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 caspase-3 activation, increased the ratio of Bcl-2/Bax, and ameliorated synaptic dysfunction by promoting dendritic spine generation with the upregulation of postsynaptic and presynaptic proteins (PSD95 and synaptophysin) in Aβ 1–42 -treated mice. Our results indicate that INT-777 has potent neuroprotective effects against Aβ 1–42 -induced neurotoxicity. Taken together, these findings suggest that the activation of TGR5 could be a novel and promising strategy for the treatment of AD. [ABSTRACT FROM AUTHOR]