Fig. 4: Tau pathology shunts glucose towards glutamate production while upregulating metabolic pathways.

A Experiment design for stable isotope resolved metabolomics (SIRM) following a ¹³C-labeled glucose oral gavage. B Heatmap of metabolites that are fractionally enriched following ¹³C-glucose administration in individual mice and genotype averages in 9-month P301S v WT mice. When quantified, there was increased ¹³C-labeled glutamate P301S brains compared to WT. Concurrently, there was a decrease in ¹³C-labeled GABA in P301S mice compared to WT. C Heatmap of the total abundance (¹³C-labeled and unlabeled pools) of metabolites following ¹³C-glucose gavage. The total abundance of GABA is decreased in 9-month P301S mice compared to WT. D, E GABA:Glutamate ratios in both the fractionally enriched and total abundance groups are decreased in 9-month P301S mice. F, G Gene pathway analysis following bulk RNA sequencing of 9-month P301S and WT cortical tissue post ¹³C glucose gavage yielded changes in excitatory-metabolism coupling. F SynGO pathways, including those involved in pre- and postsynaptic homeostasis, are downregulated in the P301S cortex compared to WT, as visualized by Sankey and dot plots. G Reactome pathways associated with metabolism, diseases of metabolism, and mitochondrial homeostasis are upregulated in the P301S cortex compared to WT, as visualized by Sankey and dot plots. Data reported as means ± SEM. n = 7–8 mice/group. Significance determined using unpaired t test. Enrichr was used for pathways analysis of DEGs. SR Plot was used for data visualization. *p < 0.05, **p < 0.01.