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

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

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.

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

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Figure 1

Neuronal hyperactivity in APP/PS1-DM mice was significantly increased by RH.

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Neuronal hyperactivity in APP/PS1-DM mice was significantly increased by...
(A) Top, representative in vivo 2-photon Ca2+ images of Cal 520 loading (green) layer 2/3 neurons in the prefrontal cortex from a 6-month-old WT, APP/PS1, STZ-induced APP/PS1-DM, and STZ-induced APP/PS1-DM-RH mice. Neurons were color-coded according to their mean activity. Black, silent neurons (0 transients/min); orange, normal neurons; red, hyperactive neurons (≥6 transients/min). Bottom, spontaneous Ca2+ transients of soma indicated in the top panel. (B) Frequency distributions of recorded neurons from WT (n = 417 neurons in 7 mice), APP/PS1 (n = 376 neurons in 7 mice), APP/PS1-DM (n = 411 neurons in 7 mice), and APP/PS1-DM-RH (n = 446 neurons in 8 mice) mice. The dashed line serves as the threshold for hyperactive neurons. (C) Mean neuronal frequencies for WT (2.136 ± 0.1226 transients/min), APP/PS1 (2.571 ± 0.1177 transients/min), APP/PS1-DM (2.814 ± 0.08978 transients/min), and APP/PS1-DM-RH (3.199 ± 0.1310 transients/min). (D) Fraction of silent, normal, and hyperactive neurons from indicated groups. The data are expressed as the mean ± SEM. The differences between groups were assessed by 1-way ANOVA followed by Dunnett’s multiple comparisons test. *P < 0.05, APP/PS1-DM versus APP/PS1; &P < 0.05 and &&&P < 0.001, WT versus APP/PS1; #P < 0.05 and ##P < 0.01, APP/PS1-DM versus APP/PS1-DM-RH; APP/PS1 versus APP/PS1-DM; NS, no significant difference. Scale bars, 200 µm.