肠道菌群经由LPS所致脑Tau及Aβ病理改变在鼠老年癫痫发生中的作用

大脑老化过程中伴随肠道菌群产生脂多糖内毒素(LPS)的增高，LPS通过TLR4受体激活小胶质细胞/巨噬细胞产生大量促炎因子，进而引起Tau及Aβ病理改变，且LPS、促炎因子和Tau及Aβ均有促痫和促老化作用。新近重要文献报道肠道菌群紊乱是老化的重要原因且与癫痫密切相关。结合我们前期研究将青年鼠粪菌移植至自发性痫样放电老年鼠可显著抑制后者自发性痫样放电，反之将老年鼠粪菌移植至青年鼠则后者出现自发性痫样放电。据此，我们假说：LPS通过TLR4受体慢性激活巨噬细胞/小胶质细胞释放促炎因子，进而导致Tau和Aβ增高，促发老年癫痫的产生。本研究应用粪菌移植、受体阻断、细胞耗竭、Tau改变等方法在“肠道菌群-LPS-TLR4-小胶质细胞/巨噬细胞-促炎因子-Tau/Aβ-神经元”传导通路相应层面进行干预，观察其对老年鼠癫痫及其干预层面下游的影响，初步明确肠道菌群改变在老年癫痫发生中的作用及其炎症机制。

Brain aging is accompanied with an increase of lipopolysaccharides (LPS) secereted from gut microbiota. LPS activates microglia/macrophages through TLR4 to produce amount of pro-inflammatory cytokines causing pathological changes of Tau and Aβ. And LPS, pro-inflammatory cytokines and Tau and Aβ all have pro-epileptic and pro-aging effects. Most recent and important literatures reported that disturbance of gut microbiota is the critical cause of aging and the disturbance of gut microbiota is closely related with epilepsy. In combination with our preliminary results that spontaneous spikes were reduced in aged mice after being transferred with fecal bacteria from young mice, whereas the seizure threshold was decreased and even the spontaneous appeared in young mice after being transferred with fecal bacteria from aged mice. Thus, we hypothesizes that LPS chronically activates macrophages/microglia via TLR4 receptor, and the macrophages/microglia then release proinflammatory cytokines to set up chronic inflammation in the brain, and the chronic brain inflammation contributes to the long-term increase of Tau and Aβ, leading to the onset of epilepsy in aged mice. In this study, fecal bacteria transferring, receptor blocking, cell depletion and Tau alterations will be applied to intervene the signal transduction at variant levels of the pathway: “gut microbiota - LPS - TLR4 - microglia/macrophages - proinflammatory cytokines - Tau/Aβ - neurons ". Effect of this intervention on epilepsy and on alterations of the downstream of the intervention level will be observed to clarify the role of gut microbiota alterations in epilepsy onset in aged mice and to clarify the underlying inflammatory mechanisms of the epilepsy onset caused by gut microbiota alterations in aged mice.