Sitagliptin通过microbiota-gut-brain轴在2型糖尿病致阿尔茨海默样变中的脑保护作用机制

Type 2 diabetes mellitus increase risk for Alzheimer’s disease. It was reported that the gut microbiota of T2D patients was characterized with low level of SCFA-producing bacteria and high level of LPS .The current study showed the level of LPS and component of Coli were higher in AD brain compared to controls.Microbial production of SCFAs was reported to decrease blood-brain barrier permeability by upregulating expression of the tight junction proteins, which are known to control barrier function in endothelial tissues， and promote microglial immune response. Furthermore, amplification of regulatory T cells could restore cognitive funtions in AD model,which suggested that intestinal microbiome dysbiosis could be a key modulator of T2DM induced AD-like lesion. However,the molecular mechanism for this association remain unclear. Our previous studies showed Sitagliptin could attenuate brain injury in T2DM induced AD-like lesion model, accompanied with increased level of intestinal SCFA .We hypothesize Sitagliptin ameliorates brain injury in T2D induced AD-like lesion via microbiota-gut-brain axis triggered by SCFA-producing bacteria.. We will investigate the neuroprotective effect of Sitagliptin on T2DM induced AD-like lesion model by in vitro and in vivo experiments. The effect of Sitaglipin on gut microbiota and its neuroprotection will be first observed. Then, whether the effects of Sitaglipint are mediated by integrated blood brain barrier and activated microglia which controlled by Treg- TGFβ1 pathway trigerred by SCFA will be examed. Our project will explore the molecular mechanism of neuroprotection of Sitagliptin from a new sight and elucidate the multiple protective mechanisms of Sitagliptin on prevention and treatment of T2DM induced AD-like lesion.

2型糖尿病(T2DM)是阿尔茨海默病(AD)发病的高危因素。有研究发现T2DM患者肠道产短链脂肪酸(SCFA)菌明显减少,LPS明显增多,而AD患者大脑中发现大量LPS和Coli成分；SCFA可调控血脑屏障和小胶质细胞,并刺激肠道产生Treg细胞，后者可缓解AD认知障碍，提示肠道菌群失调可能是T2DM致AD样变的关键因素，但机制不清。我们前期实验发现Sitagliptin可改善T2DM致AD样变的脑损伤，并伴产SCFA菌明显增多。我们提出：Sitagliptin通过microbiota-gut-brain轴改善由2型糖尿病致AD样变的脑损伤。本项目拟先观察其对T2DM致AD样变的脑保护作用,再分析该作用是否通过产SCFA菌介导的Treg-TGFβ1通路对血脑屏障紧密连接蛋白和小胶质细胞的调控，最终揭示Sitagliptin对脑保护作用全新的分子机制，为防治T2DM致AD样变提供新策略。