In neurodegenerative diseases including Alzheimer's disease and frontotemporal 
dementia, the protein tau is hyperphosphorylated and eventually aggregates to 
develop neurofibrillary tangles. Here, the consequences of tau 
hyperphosphorylation on both neuronal and astrocytic metabolism and amino-acid 
neurotransmitter homeostasis were assessed in transgenic mice expressing the 
pathogenic mutation P301L in the human tau gene (pR5 mice) compared with 
nontransgenic littermate controls. Mice were injected with the neuronal and 
astrocytic substrate [1-(13)C]glucose and the astrocytic substrate 
[1,2-(13)C]acetate. Hippocampus and cerebral cortex extracts were analyzed using 
(1)H and (13)C nuclear magnetic resonance spectroscopy, gas chromatography-mass 
spectrometry and high-performance liquid chromatography. The glutamate level was 
reduced in the hippocampus of pR5 mice, accompanied by reduced incorporation of 
(13)C label derived from [1-(13)C]glucose in glutamate. In the cerebral cortex, 
glucose utilization as well as turnover of glutamate, glutamine, and GABA, were 
increased. This was accompanied by a relative increase in production of 
glutamate via the pyruvate carboxylation pathway in cortex. Overall, we revealed 
that astrocytes as well as glutamatergic and GABAergic neurons in the cortex of 
pR5 mice were in a hypermetabolic state, whereas in the hippocampus, where 
expression levels of mutant human tau are the highest, glutamate homeostasis was 
impaired.