Glutamate metabolism is impaired in transgenic mice with tau hyperphosphorylation
Open accessAbstract
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.
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A recent study reported increased glucose utilisation and hyper-metabolism in the cortex in the same mouse model.
“This finding is supported by a recent study that reported increased glucose utilisation and hyper-metabolism in the cortex in the same mouse model (Nilsen et al., 2013).”
From In vivo imaging of tau pathology using multi-parametric quantitative MRI (2015) · cites this paper as Nilsen et al., 2013
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“In addition to A -induced changes of GABAergic transmission, abnormal activation of GABAergic system was also found to participate in the hyperphosphorylation of tau and the formation of neurofibrillary tangles (Nykänen et al., 2012; Nilsen et al., 2013).”
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Yang, Y., & Wang, J. (2021) · Neuroscience Bulletin · doi:10.1007/s12264-021-00716-6 · Cited by 23 · see citing works
Patel, A. B., Tiwari, V., Veeraiah, P., & Saba, K. (2017) · Journal of Cerebral Blood Flow and Metabolism · doi:10.1177/0271678x17709463 · Cited by 25 · see citing works
Papegaey, A., Eddarkaoui, S., Deramecourt, V., Fernández-Gómez, F.-J., Pantano, P., Obriot, H., Machala, C., Anquetil, V., Camuzat, A., Brice, A., et al. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0345-0 · Cited by 19 · see citing works
“This astrocytic enzyme that converts glutamate into glutamine is frequently deregulated in neurodegenerative diseases presenting with Tau modification [68, 69].”
BackgroundPuma, D. D. L., Ripoli, C., Puliatti, G., Pastore, F., Lazzarino, G., Tavazzi, B., Arancio, O., Piacentini, R., & Grassi, C. (2022) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12811 · Cited by 28 · see citing works
The associations of serum valine with mild cognitive impairment and Alzheimer’s disease
Xiong, Y., Therriault, J., Ren, S., Jing, X., & Zhang, H. (2021) · Aging Clinical and Experimental Research · doi:10.1007/s40520-022-02120-0 · Cited by 21 · see citing works
“In transgenic mice expressing the pathogenic mutation P301L in the human tau gene (pR5 mice), astrocytes as well as glutamatergic and GABAergic neurons in the cortex were in a hypermetabolic state, whereas in the hippocampus, where expression levels of mutant human tau are the highest, glutamate levels were reduced an…”
BackgroundFrontotemporal Dementia and Glucose Metabolism
Garrett, L. R., & Niccoli, T. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.812222 · Cited by 20 · see citing works
Borreca, A., Latina, V., Corsetti, V., Middei, S., Piccinin, S., Valle, F. D., Bussani, R., Ammassari‐Teule, M., Nisticò, R., Calissano, P., et al. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-0974-3 · Cited by 18 · see citing works
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“Interestingly, cortical GABAergic interneurons are in a hypermetabolic state in a mouse model of FTD (Nilsen et al., 2013).”
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Rather, M. A., Khan, A., Jahan, S., Siddiqui, A. J., & Wang, L. (2024) · Neuroscience · doi:10.1016/j.neuroscience.2024.05.042 · Cited by 16 · see citing works
Frontotemporal Lobar Degeneration: Mechanisms and Therapeutic Strategies
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Magnetic Resonance Imaging in Tauopathy Animal Models
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Glial Cells in Alzheimer’s Disease: Pathogenic Mechanisms and Therapeutic Frontiers
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“They observed that Aβ entered wild-type grafts alongside microglial accumulation, along with that the in vivo imaging demonstrated that microglia acted as carriers of Aβ burden into earlier healthy tissue (Nilsen et al. 2013, Nishiyama et al. 1991) (Fig.”
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“In the hippocampus of P301L (pR5) mice, where expression levels of mutant tau are greatest, overall glutamate homeostasis was found to be disrupted with significant reduction in glutamate levels [81].”
Nicoli, A. L., Abed, A. S. A., Hulme, S. R., Das, A., Gauthier-Coles, G., Bröer, A., Balkrishna, S., Burgio, G., Dehorter, N., Rae, C. D., et al. (2025) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2025.102785 · Cited by 10 · see citing works
“…and Slc6a17 -/- mice were injected subcutaneously with 10 µ L / g [1-13 C] D-glucose (0.3 M; CLM-420-MPT-PK, Cambridge Isotope Laboratories) and [1,2-13 C] acetate (0.6 M; CLM-440-MPT-PK, Cambridge Isotope Laboratories) 15 minutes prior to decapitation without anaesthetic (Nilsen et al., 2013).”
InfluentialSelf-citationHernández-Contreras, K. A., Hernández-Aguilar, M. E., Herrera-Covarrubias, D., Rojas-Durán, F., & Aranda-Abreu, G. (2021) · Revista Mexicana de Neurociencia · doi:10.24875/rmn.20000087 · Cited by 5 · see citing works
Brain metabolic and functional alterations in a liver-specific PTEN knockout mouse model
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SIRT2 transgenic over‐expression does not impact lifespan in mice
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“…this, we traced the metabolism of 13 C isotope labelled glucose and acetate into the cerebral cortex of SIRT2-Tg and WT littermates as previously described (Nilsen et al., 2013), measuring both 13 C label incorporation and total metabolite levels using 1 H and 13 C NMR spectroscopy (Figure 5).”
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“Increased glucose metabolism has been reported prior to proteinopathy in AD mouse models [47, 97] and correlated to cognitive dysfunction severity in PD patients [7].”
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Okada, M., Yanamoto, K., Kagawa, T., Yoshino, K., Hosoi, R., Abe, K., Zhang, M.-R., & Inoue, O. (2016) · Journal of Cerebral Blood Flow and Metabolism · doi:10.1177/0271678x15606144 · Cited by 1
“However, MRS itself requires the infusion of large amounts of [(13)C]acetate, which may affect normal physiological conditions.(9,10) On the other hand, (14)C-labeled acetate is used to measure astrocytic energy metabolism in rats and mice with trace amounts of substrates,(11) although”
BackgroundPapegaey, A. (2016) · doi:10.70675/3ca42b8dz3ed3z4d20z9ac2z0a2c5bd79786
“En effet, cette enzyme de l’astrocyte, qui sert à convertir le glutamate en glutamine, est retrouvée fréquemment dérégulée dans des maladies neurodégénératives impliquant une altération de la protéine Tau (Hege Nilsen et al., 2013; Kulijewicz-Nawrot et al., 2013).”
- Authors
- Nilsen, L. H., Rae, C., Ittner, L. M., Götz, J., & Sonnewald, U.
- Affiliations
- Norwegian University of Science and Technology (NO)
- UNSW Sydney (AU)
- The University of Sydney (AU)
- Corresponding author
- Sonnewald, Ursula
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2013-01-23
- Volume
- 33
- Issue
- 5
- Pages
- 684-691
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC3652703
- OpenAlex
- W2058829280
- Cited by
- 62
- References
- 40
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 5 · 2020: 4 · 2019: 2 · 2018: 2 · 2017: 6 · 2016: 8 · 2015: 8 · 2014: 3 · 2013: 5
- FWCI
- 5.57
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Nasjonalforeningen for Folkehelsen
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- tau hyperphosphorylation, P301L tau mutation, glutamate metabolism, glutamate homeostasis, astrocyte metabolism, neuronal metabolism, glucose metabolism, pyruvate carboxylation, glutamine, GABA, hippocampus, cerebral cortex, neurodegeneration, Alzheimer's disease, frontotemporal dementia, transgenic mice
- MeSH terms
- Acetates, Animals, Astrocytes, Cerebellar Cortex, Dementia, Female, gamma-Aminobutyric Acid, Glucose, Hippocampus, Humans, Male, Mice, Transgenic, Mutation, Neurons, Phosphorylation, tau Proteins, Neurotransmitter Agents, Glutamic Acid, Transgenes, Mice
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