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

Chengkang He,Hongbo Jia,Li Li,Hongting Zheng,Yuanting Cui,Daoyan Liu,Wentao Shu,Yu Zhao,Huan Ma,Peng Gao,Xiaowei Chen,Qing Zhou,Martin Tepel,Zhiming Zhu,Qiang Li,Zongshi Lu,Lijuan Wang,Gangyi Yang

doi:10.1172/jci.insight.154595

Abstract

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

Highlights

Determinants of accelerated cognitive decline in diabetic patients with genetic susceptibility to Alzheimer’s disease (AD) are less clear because glucose dyshomeostasis is complex and can range from chronic hyperglycemia to treatment-induced recurrent hypoglycemia or be combined with hypertension and cardiovascular complications
Here, we demonstrate that 8 weeks of recurrent moderate hypoglycemia (RH) treatment dramatically aggravates cortical hyperactivity, that it promotes the progression of cognitive deficits in diabetic APP/PS1 mice, and that it significantly impairs GLUT3-mediated neuronal glucose uptake, which is associated with neuronal transient receptor potential channel 6 (TRPC6) dysfunction
These data suggest that RH is a potent risk factor that can facilitate AD development and that TRPC6 might be a potential target for alleviating hypoglycemia-associated cognitive impairment

Summary

Introduction

Determinants of accelerated cognitive decline in diabetic patients with genetic susceptibility to AD are less clear because glucose dyshomeostasis is complex and can range from chronic hyperglycemia to treatment-induced recurrent hypoglycemia or be combined with hypertension and cardiovascular complications. As GLUT-3-mediated glucose transport into neurons is metabolized in mitochondria to produce ATP, and mitochondrial dysfunction is causally associated with dementia [2, 24, 25], the question is whether RH can affect the expression and function of brain GLUTs and further impair brain mitochondrial function. We have recently shown that a RH-induced reduction in TRPC6 expression led to cognitive impairment under diabetic conditions by impairing hippocampal mitochondrial function[28]. It is unknown whether RH promotes the development of cognitive deficits in diabetic APP/PS1 mice. This study examined if and how RH participates in the progression of AD-type pathology and cognitive deficits in diabetic APP/PS1 mice

Methods

Results

Conclusion