Glutamate Metabolism is Impaired in Transgenic Mice with Tau Hyperphosphorylation

Abstract

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.

Hypermetabolic State in the 7-Month-Old Triple Transgenic Mouse Model of Alzheimer'S Disease and the Effect of Lipoic Acid: A 13C-NMR Study

“…[37][38][39] In addition to the association of hypermetabolism with plaques, a metabolic study in the tau transgenic mouse model of AD showed hypermetabolism in cerebral cortex. 19 Concluding Remarks The major finding of this study is the hypermetabolic state in the 7-month-old 3xTg-AD mice as compared with age-matched nonTg mice and these results are in contrast to the hypometabolism observed in 13-month-old 3xTg-AD mice. Importantly, the specific role of metabolism in the coordinated picture of hyperactivity (electrophysiologic and physiologic), previously reported in multiple mouse models of AD was highlighted.…”

Differential effects of ethanol on regional glutamatergic and GABAergic neurotransmitter pathways in mouse brain

“…A short period infusion of acetate has been used to evaluate energy metabolism of astrocytes in many studies (Chowdhury et al 2012;Nilsen et al 2013). In fact, the labeling of glutamine-C4 from 15 min of [2- 13 C]acetate infusion in this study is~12%, which is significant amount to identify ethanol-related alteration in the astroglial flux.…”

Reversal of Metabolic Deficits by Lipoic Acid in a Triple Transgenic Mouse Model of Alzheimer's Disease: A 13C NMR Study

“…These results further substantiate the metabolic alterations present in the different Alzheimer's disease rodent models. [30][31][32][33] Magnetic resonance studies conducted in the APP-PS1 model of Alzheimer's disease show decreased NAA and Glu, 30 along with an increase of MI. 34 A systematic evaluation on the APP-PS1 model found the ratio of choline to creatine (in the cortical and subcortical areas) as a noninvasive biomarker in these mice but did not find the utility of Glu, Gln, and MI as biomarkers.…”