Human tau promotes Warburg effect–like glycolytic metabolism under acute hyperglycemia conditions

The neurofilaments formed by hyperphosphorylated tau is a hallmark of tauopathies. However, the biological functions of tau and the physiological significance of its phosphorylation are still not fully understood. By using human tau (441 a.a.) transgenic (hTau) mice, murine tau KO mice, and C57BL/6J (C57) mice, unexpectedly, we found that under acute hyperglycemia conditions, JNK but not previously reported GSK3β mediated tau phosphorylation. Moreover, Akt, the inhibitory kinase upstream of GSK3β, was activated in a tau-dependent manner. Furthermore, under acute high glucose conditions, the presence of human tau significantly augmented Akt activation but inhibited 4E-BP1 phosphorylation simultaneously, indicating that human tau is also involved in regulating the alternative activation of mTORC1/2. By comparing the hippocampal membrane-associated proteome, we found that human tau influenced the homeostasis of protein-membrane association under acute hyperglycemia conditions. Of note, with respect to C57 and Tau KO mice, the membrane association of oxidative phosphorylation-related proteins was impeded by human tau in the hippocampus. In vitro study consistently showed that aerobic glycolysis was promoted in the presence of human tau under high glucose conditions, which maintained the ratio of NAD⁺/NADH. On the other hand, human tau restricted the level of oxidative phosphorylation, modulated the activity of SDH, and reduced ROS production upon high glucose challenging. In summary, the current study revealed that human tau played an important role in regulating glycolytic metabolism under acute hyperglycemia conditions, which is similar with the Warburg effect, through influencing the homeostasis of protein-membrane association.