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Altered brain arginine metabolism in a mouse model of tauopathy

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Abstract

Tauopathies consist of intracellular accumulation of hyperphosphorylated and aggregated microtubule protein tau, which remains a histopathological feature of Alzheimer’s disease (AD) and frontotemporal dementia. l-Arginine is a semi-essential amino acid with a number of bioactive molecules. Its downstream metabolites putrescine, spermidine, and spermine (polyamines) are critically involved in microtubule assembly and stabilization. Recent evidence implicates altered arginine metabolism in the pathogenesis of AD. Using high-performance liquid chromatographic and mass spectrometric assays, the present study systematically determined the tissue concentrations of l-arginine and its nine downstream metabolites in the frontal cortex, hippocampus, parahippocampal region, striatum, thalamus, and cerebellum in male PS19 mice-bearing human tau P301S mutation at 4, 8, and 12–14 months of age. As compared to their wild-type littermates, PS19 mice displayed early and/or prolonged increases in l-ornithine and altered polyamine levels with age. There were also genotype- and age-related changes in l-arginine, l-citrulline, glutamine, glutamate, and γ-aminobutyric acid in a region- and/or chemical-specific manner. The results demonstrate altered brain arginine metabolism in PS19 mice with the most striking changes in l-ornithine, polyamines, and glutamate, indicating a shift of l-arginine metabolism to favor the arginase–polyamine pathway. Given the role of polyamines in maintaining microtubule stability, the functional significance of these changes remains to be explored in future research.

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Acknowledgements

This work was supported by the Beth Cobden-Cox Research Grant, and Brain Health Research Centre and Department of Anatomy, University of Otago, New Zealand. The authors would also like to thank the technical staff in the Department of Anatomy and School of Pharmacy, University of Otago, for their assistance. Pranav Vemula is a recipient of the University of Otago Postgraduate Scholarship.

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Authors and Affiliations

  1. Department of Anatomy, School of Biomedical Sciences, Brain Health Research Centre, University of Otago, Dunedin, New Zealand

    Pranav Vemula, Yu Jing & Ping Liu

  2. School of Pharmacy, Brain Health Research Centre, University of Otago, Dunedin, New Zealand

    Hu Zhang & Ping Liu

  3. Brain Research New Zealand, Dunedin, New Zealand

    Pranav Vemula, Yu Jing, Hu Zhang & Ping Liu

  4. Byrd Alzheimer’s Institute, College of Pharmacy and Pharmaceutical Sciences, University of South Florida, Florida, USA

    Jerry B. Hunt Jr., Leslie A. Sandusky-Beltran & Daniel C. Lee

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  1. Pranav Vemula
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Vemula, P., Jing, Y., Zhang, H. et al. Altered brain arginine metabolism in a mouse model of tauopathy. Amino Acids 51, 513–528 (2019). https://doi.org/10.1007/s00726-018-02687-x

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