目的:胃旁路手术已被证明可以通过GLP1改善代谢状况,这也可能对阿尔茨海默病(AD)患者具有认知益处。然而,确切的机制需要进一步调查。
方法:对APP/PS1/Tau三重转基因小鼠(AD小鼠模型)或野生型C57BL/6小鼠进行Roux-en-Y胃旁路手术或假手术。使用Morris水迷宫(MWM)测试来评估小鼠的认知功能,并且在手术后两个月获得动物组织样品用于测量。此外,用siTAS1R2和siSGLT1处理STC-1肠细胞,用Aβ处理HT22神经细胞,siGLP1R,通过对GLP1和siSGLT1的体外实验探讨GLP1-SGLT1相关信号通路在认知功能中的作用。
结果:MWM测试表明,如导航和空间探针测试所测量,搭桥手术显着改善了AD小鼠的认知功能。此外,旁路手术逆转了神经变性,Tau蛋白过度磷酸化和Aβ沉积下调,改善葡萄糖代谢,并上调海马中GLP1、SGLT1和TAS1R2/3的表达。此外,GLP1R沉默下调SGLT1表达,而SGLT1沉默增加了Tau蛋白沉积并加剧了HT22细胞中葡萄糖代谢的失调。然而,RYGB不会改变脑干(主要产生中央GLP1)中GLP1分泌的水平。此外,在小肠中,经由TAS1R2/3-SGLT1的激活顺序地由RYGB上调GLP1表达。
结论:RYGB手术可通过促进糖代谢,减少海马tau磷酸化和Aβ沉积,改善AD小鼠的认知功能。外周血清GLP1介导脑内SGLT1的活化。此外,RYGB通过依次激活小肠中的TAS1R2/TAS1R3和SGLT1增加GLP1表达。
Gastric bypass surgery has been shown to improve metabolic profiles via GLP1, which may also have cognitive benefits for Alzheimer\'s disease (AD) patients. However, the exact mechanism requires further investigation.
Roux-en-Y gastric bypass or sham surgery was performed on APP/PS1/Tau triple transgenic mice (an AD mice model) or wild type C57BL/6 mice. Morris Water Maze (MWM) test was used to evaluate the cognitive function of mice and animal tissue samples were obtained for measurements two months after the surgery. Additionally, STC-1 intestine cells were treated with siTAS1R2 and siSGLT1, and HT22 nerve cells were treated with Aβ, siGLP1R, GLP1 and siSGLT1 in vitro to explore the role of GLP1-SGLT1 related signaling pathway in cognitive function.
The MWM test showed that bypass surgery significantly improved cognitive function in AD mice as measured by navigation and spatial probe tests. Moreover, bypass surgery reversed neurodegeneration, down-regulated hyperphosphorylation of Tau protein and Aβ deposition, improved glucose metabolism, and up-regulated the expression of GLP1, SGLT1, and TAS1R2/3 in the hippocampus. Furthermore, GLP1R silencing down-regulated SGLT1 expression, whereas SGLT1 silencing increased Tau protein deposition and exacerbated dysregulated of glucose metabolism in HT22 cells. However, RYGB did not alter the level of GLP1 secretion in the brainstem (where central GLP1 is mainly produced). Additionally, GLP1 expression was upregulated by RYGB via TAS1R2/3-SGLT1 activation sequentially in the small intestine.
RYGB surgery could improve cognition function in AD mice through facilitating glucose metabolism and reducing Tau phosphorylation and Aβ deposition in the hippocampus, mediated by peripheral serum GLP1 activation of SGLT1 in the brain. Furthermore, RYGB increased GLP1 expression through sequential activation of TAS1R2/TAS1R3 and SGLT1 in the small intestine.