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 considered as a potential target for alleviating or treating DACD in the future.
Highlights
Diabetes mellitus causes brain structure changes and cognitive decline, and it has been estimated that diabetes doubles the risk for dementia
By nuclear magnetic resonance (NMR)-based metabolomics, we have previously shown that the development of diabetes-associated cognitive decline (DACD) is related to alterations in glucose metabolism and to the impaired glutamate-glutamine cycle in the hippocampus of the diabetic dyslipidemia mouse model [19]
It was revealed that Montreal cognitive assessment scores of clinical subjects were negatively correlated to lactate levels in the cerebrospinal fluid but not in the blood, strongly suggesting that excess cerebral lactate is related to cognitive decline [43]
Summary
The study reveals in chronic diabetes conditions, excess lactate secretion in hippocampus play an inhibitory function on cognition ability, through lactate receptor (GPR81)-depended mechanism. We report that progressively increasing lactate levels is an important pathogenic factor in DACD, directly linking diabetes to cognitive dysfunction. Metabolomic analysis is an important platform used to measure and identify key metabolites related to pathological conditions It has been extensively applied for the exploration of potential biomarkers and has provided crucial insights into the pathogenesis of diseases [13,14,15,16]. We found that the anaerobic glycolysis metabolite lactate is significantly elevated in a time-dependent manner in hippocampal extracts of rats with streptozotocin (STZ)-induced diabetes. We confirmed elevated glycolysis in the hippocampus of diabetic rats by measuring the activity and the expression levels of lactate dehydrogenase-A (LDH-A). The possibility that astrocytes release excess lactate in diabetic conditions, which could affect learning and memory, was explored
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