Human tau promotes Warburg effect-like glycolytic metabolism under acute hyperglycemia conditions through modulating the homeostasis of protein-membrane association

The neurofilaments formed by hyperphosphorylated tau is a hallmark of tau-related neurodegenerative disease, including Alzheimers disease, tau related FTDP-17, Picks disease, et al. 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 in which murine tau has been deleted simultaneously, murine tau knockout (Tau KO) mice and C57BL/6J (C57) mice, unexpectedly, we found that under acute hyperglycemia conditions, JNK but not previously reported GSK-3{beta} mediated tau phosphorylation. Moreover, Akt, the upstream GSK-3{beta} inhibitory kinase, was activated in a tau dependent manner. By comparing the membrane-associated proteome, we found that human tau influenced the homeostasis of protein-membrane association under acute hyperglycemia conditions. Of note, with respect to WT and Tau KO mice, the membrane-association of Krts, TFAM, TRAP1, mTOR et al, were strengthened by human tau. Whereas, the membrane-association of ribosomal proteins Rpls, proteasome proteins Psmds, and mitochondrial proteins, such as COXs, Ndufa1, Mtnt4, et al, were impeded by human tau. In vitro study showed that aerobic glycolysis was promoted in the presence of human tau, which maintained NAD+/NADH ratio. On the other hand, it restricted oxidative phosphorylation level, modulated the activity of SDH, and reduced ROS production upon challenging by high glucose. Furthermore, under acute high glucose conditions, the presence of human tau significantly augmented Akt activation, but inhibited 4EBP phosphorylation simultaneously, indicating that human tau is also involved in regulating the alternative activation of mTORC1/2. In summary, the current study revealed that human tau played an important role in regulating glycolytic metabolism under acute high hyperglycemia conditions, which is similar with the Warburg-effect, through influencing the homeostasis of protein-membrane association.