High glucose impairs cognitive function through Creb3 O-GlcNAcylation and increased lactate production

The high glucose levels characteristic of diabetes can lead to increases in glucose metabolism through the process of glycolysis, resulting in greater production of lactate and in a monosaccharide-based posttranslational modification called O-GlcNAcylation. Here, we identified O-GlcNAcylation and lactate production as the molecular mechanisms underlying high glucose-induced cognitive impairment, a prevalent complication of diabetes. A prospective observational study revealed that elevated plasma concentrations of lactate were an independent risk factor for predicting mild cognitive impairment in patients with diabetes. High-glucose treatment of mouse hippocampal neurons increased the O-GlcNAcylation of the transcription factor Creb3, which stabilized the protein by preventing its ubiquitination. The increase in Creb3 subsequently up-regulated the expression of the downstream target gene Ldha, which encodes the enzyme lactate dehydrogenase. As a result, lactate production was increased during glycolysis, triggering neuronal apoptosis and cognitive dysfunction in mouse models of type 1 and 2 diabetes. Expression of a Creb3 mutant that could not be O-GlcNAcylated at Ser³²⁵ or competitive blockade of the O-GlcNAcylation of Ser³²⁵ in Creb3 with a short peptide alleviated these effects. This study elucidates a mechanistic link between high glucose-induced Creb3 O-GlcNAcylation and Ldha-mediated lactate production, offering a potential therapeutic strategy for managing diabetes-related cognitive dysfunction.