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

Brain Behav Immun. 2018 Oct:73:533-545. doi: 10.1016/j.bbi.2018.06.018. Epub 2018 Jun 20.

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 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 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 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 the activation of TGR5 could be a novel and promising strategy for the treatment of AD.

Keywords: Alzheimer’s disease; Apoptosis; Aβ(1–42); Cognitive; INT-777; Memory; Neuroinflammation; Neurotoxicity; Synaptic dysfunction; TGR5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / adverse effects
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Apoptosis / drug effects
  • Brain / metabolism
  • Caspase 3 / metabolism
  • Cholic Acids / metabolism
  • Cholic Acids / pharmacology*
  • Cognitive Dysfunction / drug therapy
  • Disease Models, Animal
  • Hippocampus / metabolism
  • Male
  • Maze Learning / drug effects
  • Memory / drug effects
  • Memory Disorders / metabolism
  • Mice
  • Mice, Inbred ICR
  • Neuroimmunomodulation / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology
  • Peptide Fragments / adverse effects
  • Peptide Fragments / metabolism

Substances

  • 6alpha-ethyl-23(S)-methylcholic acid
  • Amyloid beta-Peptides
  • Cholic Acids
  • Neuroprotective Agents
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Caspase 3