Recurrent moderate hypoglycemia accelerates the progression of Alzheimer’s disease through impairment of the TRPC6/GLUT3 pathway

• DOI: 10.1172/jci.insight.154595
• Publication Date: 2022-01-25T17:05:04Z
• Authors: Chengkang He; Qiang Li; Yuanting Cui; Peng Gao; Wentao Shu; Qing Zhou; Lijuan Wang; Li Li; Zongshi Lu; Yu Zhao; Huan Ma; Xiaowei Chen; Hongbo Jia; Hongting Zheng; Gangyi Yang; Daoyan Liu; Martin Tepel; Zhiming Zhu
• Keywords: GLUT3; Cognitive Decline

Currently, the most effective strategy for dealing with Alzheimer's disease (AD) is delaying onset of dementia. Severe hypoglycemia strongly associated dementia; however, effects recurrent moderate (RH) on progression cognitive deficits in patients diabetes genetic susceptibility to AD remain unclear. Here, we report that insulin-controlled hyperglycemia slightly aggravated AD-type pathologies and impairment; RH significantly increased neuronal hyperactivity accelerated streptozotocin-induced (STZ-induced) diabetic APP/PS1 mice. Glucose transporter 3-mediated (GLUT3-mediated) glucose uptake was not altered under but markedly reduced by RH, which induced excessive mitochondrial fission hippocampus. Overexpression GLUT3, specifically dentate gyrus (DG) area hippocampus, enhanced function improved deficits. Activation transient receptor potential channel 6 (TRPC6) GLUT3-mediated brain alleviated RH-induced deficits, inactivation Ca2+/AMPK pathway responsible TRPC6-induced GLUT3 inhibition. Taken together, impairs further provokes dysfunction inhibiting TRPC6 expression, then accelerates Avoiding essential glycemic control diabetes, TRPC6/GLUT3 represents potent targets dementia diabetes.