Sirtuin-1通过“肠-脑轴”调控脑类淋巴通道在运动训练改善AD小鼠认知功能中的作用及机制

As the major pathological character of Alzheimer’s disease, Aβ deposition is related to glymphatic dysfunction. “Gut-brain axis” aggravates the Aβ accumulation, but the mechanism has kept unknown. We previously found that: exercise accelerates the glymphatic clearance and decreases the Aβ deposits; T cells derived from gut were found in the meninges, which induced brain inflammation. The preliminary experiment showed that: Intestinal apoptosis associated speck-like protein (ASC) damaged the meningeal lymphoid endothelial cells and impaired the cognition in aged mice. Exercise increased the expression of Sirtuin-1 and improved cognition regulated by “gut-brain axis”. Therefore, we propose that: By activating sirtuin-1 signaling, Exercise inhibits the ASC activation, accelerates the glymphatic clearance and improves the cognition in AD mice. In this project, we will use APP/PS1 transgenic mice to induced the “gut-brain axis” training model, to elaborate the effect of physical training on the activation of ASC in “gut-brain axis” as well as on the cognition impaired by “gut-brain axis”, and define the mechanism of sirtuin-1. Our results will provide evidence for exercise is an effective treatment for cognition impairment in AD patients.

作为阿尔茨海默病（AD）的主要病理特征，Aβ异常沉积与脑类淋巴通道功能障碍有关。“肠-脑轴”可促进Aβ沉积，但机制不清。前期研究发现：运动训练促进类淋巴通道功能，减少Aβ沉积；肠道T淋巴细胞可在脑膜聚集并介导脑内炎症反应。预实验结果显示：肠道凋亡相关微粒蛋白（ASC）损伤脑膜淋巴内皮细胞，损害老年小鼠认知功能；运动训练增加Sirtuin-1蛋白的表达，改善“肠-脑轴”介导的认知功能障碍。因此，我们假设：运动训练可通过Sirtuin-1蛋白降低“肠-脑轴”中ASC的活性，提高Aβ经脑类淋巴通道清除效率，进而改善AD小鼠的认知功能。本研究拟采用APP/PS1转基因小鼠制备“肠-脑轴”运动训练模型，探讨运动训练是否通过抑制ASC活性，改善“肠-脑轴”介导的小鼠认知功能障碍，并明确Sirtuin-1蛋白的作用机制。研究结果可为深入阐明运动训练改善AD认知功能的机制及优化AD的康复策略提供依据。

研究背景：作为阿尔茨海默病（AD）的主要病理特征，Aβ异常沉积与脑类淋巴通道功能障碍有关。“肠-脑轴”可促进Aβ沉积，肠道T淋巴细胞可在脑膜聚集并介导脑内炎症反应，加重AD认知障碍，但机制不清。.研究内容：采用CX3CR1CreER/+:NLRP3flfl/fl、NLRP3基因敲除小鼠、5xFAD阿尔茨海默病转基因动物模型，通过腹腔注射LPS制备全身系统性炎症模型和右旋糖酐硫酸酯钠制备的慢性肠道炎症模型，研究“肠-脑轴”在脑类淋巴清除系统功能中的昨天和脑膜T淋巴细胞聚集的调控机制。进一步通过自主运动训练模型，研究运动训练的阿尔茨海默认知功能的改善作用及Sirtuin-1蛋白的参与。.重要研究结果和关键数据：1）采用老年野生型小鼠和NLRP3 KO小鼠，发现慢性肠道炎症可介导野生型老年小鼠的类淋巴清除功能障碍（P < 0.001）、加重脑内Aβ沉积 (P < 0.05)，而NLRP3 KO小鼠的类淋巴清除功能无明显影响 (P>0.05)。2）慢性肠道炎症增加脑内NLRP3/ASC炎症小体的表达及激活(P < 0.05)，NLRP3基因敲除可改善“肠-脑轴”对脑内类淋巴清除代谢、Aβ沉积及认知功能的不良影响。3）通过他莫昔芬诱导特异性基因敲除小胶质细胞的NLRP3（P < 0.0001），外周腹腔注射LPS，发现LPS可加重老年脑内类淋巴清除功能障碍，促进老年小鼠认知功能障碍，而特异性基因敲除小胶质细胞NLRP3可减轻外周炎症介导的脑损伤（P < 0.01）。4）慢性肠道炎症加重5xFAD小鼠脑内Aβ42斑块沉积，而运动训练可减少脑内Aβ斑块沉积、增加Sirtuin-1蛋白的表达，减少NLRP3、ASC表达。.重要结论：运动训练可通过Sirtuin-1蛋白降低“肠-脑轴”中ASC的活性，提高Aβ经脑类淋巴通道清除效率，减轻老年肠炎相关认知功能障碍。.科学意义：深入阐明运动训练改善AD认知功能的机制，为临床优化AD的康复策略提供依据。