Metabolomic Analysis Identifies Lactate as an Important Pathogenic Factor in Diabetes-associated Cognitive Decline Rats.

Molecular & Cellular Proteomics : MCP
Liangcai ZhaoHongchang Gao

Abstract

Diabetes mellitus causes brain structure changes and cognitive decline, and it has been estimated that diabetes doubles the risk for dementia. Until now, the pathogenic mechanism of diabetes-associated cognitive decline (DACD) has remained unclear. Using metabolomics, we show that lactate levels increased over time in the hippocampus of rats with streptozotocin-induced diabetes, as compared with age-matched control rats. Additionally, mRNA levels, protein levels, and enzymatic activity of lactate dehydrogenase-A (LDH-A) were significantly up-regulated, suggesting increased glycolysis activity. Importantly, by specifically blocking the glycolysis pathway through an LDH-A inhibitor, chronic diabetes-induced memory impairment was prevented. Analyzing the underlying mechanism, we show that the expression levels of cAMP-dependent protein kinase and of phosphorylated transcription factor cAMP response element-binding proteins were decreased in 12-week diabetic rats. We suggest that G protein-coupled receptor 81 mediates cognitive decline in the diabetic rat. In this study, we report that progressively increasing lactate levels is an important pathogenic factor in DACD, directly linking diabetes to cognitive dysfunction. LDH-A may be ...Continue Reading

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Citations

May 30, 2020·International Journal of Molecular Sciences·Krish ChandrasekaranJames William Russell
Jan 30, 2019·Frontiers in Cellular Neuroscience·Minjian DongHongchang Gao
Mar 13, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yixin CuiYu Sun
Nov 20, 2021·Experimental Biology and Medicine·Sara M MohamedMarwa S Khattab

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