TMAO promotes dementia progression by mediating the PI3K/Akt/mTOR pathway

Abstract

Background: Dementia poses a serious threat to the daily and social abilities of patients, and trimethylamine-N-oxide (TMAO) is a metabolite of the gut microbiota involved in regulating the inflammatory response. However, the role of TMAO in dementia needs further investigation. This study aimed to investigate the effects and possible mechanisms of TMAO on dementia, which may provide ideas for the treatment of dementia.

Materials and methods: Dementia mice were induced by D-galactose + AlCl₃, and the changes in learning memory capacity, histopathology, inflammatory factors, and PI3K/Akt/mTOR in mice treated with TMAO were analyzed to determine the mechanism of TMAO action on dementia. In addition, the effect of TMAO+PI3K inhibitor treatment on mice was also analyzed to further determine the mechanism of TMAO effect on dementia.

Results: The results revealed that the dementia group had significantly higher TMAO levels and a significant hippocampal injury and inflammatory response. TMAO treatment promoted hippocampal injury and promoted the level of inflammatory cytokines. Further study of PI3K/Akt/mTOR signaling pathway showed that the expression of p-PI3K, p-Akt, and p-mTOR was significantly increased in the dementia group, and it was more obvious after TMAO treatment. And hippocampal injury, inflammatory response, and increase of p-PI3K, p-Akt, p-mTOR were reversed by TMAO+PI3K inhibitor.

Conclusions: This study determined that TMAO promotes dementia through the PI3K/Akt/mTOR signaling pathway, suggesting that TMAO may be a potential target for dementia.

Keywords: Dementia; Hippocampal injury; Inflammatory response; PI3K/Akt/mTOR; Trimethylamine-N-oxide.