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

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.

A study on role and mechanism of TLR4/NF-κB pathway in cognitive impairment induced by cerebral small vascular disease.

OBJECTIVE: To investigate the role and potential mechanism of Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway in cognitive impairment induced by cerebral small vascular disease (CSVD), so as to provide a reference for the clinical treatment of CSVD-induced cognitive impairment. METHODS: Mice with TLR4 gene knockout (n = 20) and those with wild-type TLR4 gene (n = 40) aged 8-10 weeks old were divided into blank control group (Control group, n = 20), wild-type + CSVD group (WT + CSVD group, n = 20) and TLR4 gene knockout + CSVD group (TLR4 KO + CSVD group, n = 20). Allogeneic thrombosis (particle diameter: 50-70 mm) was injected to the mouse's external carotid artery to create a model of learning and memory dysfunction. Step-down test and Y-type maze test were utilized to examine the learning and memory abilities of the mice. Reverse transcription-polymerase chain reaction (RT-PCR) and immunoblotting techniques were adopted to measure the levels of apoptosis-related genes [B-cell lymphoma/leukemia-2 (Bcl-2), Bcl-2-associated X protein (Bax), C-caspase-3 and T-caspase-3] in the brain tissues of mice. Terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) method was applied to detect the apoptosis of neuronal cells in the brain tissues. Meanwhile, the levels of oxidative stress markers, including superoxide dismutase (SOD), gp91 and malondialdehyde (MDA), were measured. Finally, the expression level of TLR4/NF-κB pathway was detected. RESULTS: The latency in the step-down test in the WT + CSVD group was remarkably longer than that in the Control group, and the number of errors was evidently larger than that in the Control group (p < 0.05). At the same time, in the WT + CSVD group, the expression levels of pro-apoptotic genes Bax and C-caspase-3 were up-regulated markedly, while the expression level of anti-apoptotic gene Bcl-2 declined notably (p < 0.05). TUNEL results showed that the number of apoptotic cells in the brain tissues in the WT + CSVD group was about 12 times that in the Control group (p < 0.05). Meanwhile, the SOD expression level was lowered, and the MDA expression level was elevated in the brain tissues in the WT + CSVD group. In addition, the TLR4/NF-κB pathway was prominently activated in the mice in the WT + CSVD group (p < 0.05). After TLR4 gene knockout, the cognitive functions of the mice were improved markedly, and the apoptosis of neuronal cells and oxidative stress in the brain tissues were suppressed significantly in the meantime. Moreover, the activation of the TLR4/NF-κB signaling pathway was also inhibited. CONCLUSION: The TLR4/NF-κB pathway is involved in the occurrence and development of CSVD-induced cognitive impairment through regulating oxidative stress and cell apoptosis.