The effect of gastric bypass surgery on cognitive function of Alzheimer's disease and the role of GLP1-SGLT1 pathway.

OBJECTIVE

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.