Altered brain arginine metabolism in a mouse model of tauopathy
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.
KeywordsTauopathy Arginine metabolism l-Ornithine Polyamines Glutamate Hippocampus
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.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution.
- Bensemain F, Hot D, Ferreira S, Dumont J, Bombois S, Maurage CA, Huot L, Hermant X, Levillain E, Hubans C, Hansmannel F, Chapuis J, Hauw JJ, Schraen S, Lemoine Y, Buee L, Berr C, Mann D, Pasquier F, Amouyel P, Lambert JC (2009) Evidence for induction of the ornithine transcarbamylase expression in Alzheimer’s disease. Mol Psychiatry 14:106–116CrossRefGoogle Scholar
- Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, White CL 3rd, Schneider JA, Grinberg LT, Halliday G, Duyckaerts C, Lowe JS, Holm IE, Tolnay M, Okamoto K, Yokoo H, Murayama S, Woulfe J, Munoz DG, Dickson DW, Ince PG, Trojanowski JQ, Mann DM (2007) Consortium for frontotemporal lobar degeneration. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114:5–22CrossRefGoogle Scholar
- Hunt JB Jr, Nash KR, Placides D, Moran P, Selenica ML, Abuqalbeen F, Ratnasamy K, Slouha N, Rodriguez-Ospina S, Savlia M, Ranaweera Y, Reid P, Dickey CA, Uricia R, Yang CG, Sandusky LA, Gordon MN, Morgan D, Lee DC (2015a) Sustained arginase 1 expression modulates pathological tau deposits in a mouse model of tauopathy. J Neurosci 35:14842–14860CrossRefGoogle Scholar
- López-González I, Aso E, Carmona M, Armand-Ugon M, Blanco R, Naudi A, Cabre R, Portero-Otin M, Pamplona R, Ferrer I (2015) Neuroinflammatory gene regulation, mitochondrial function, oxidative stress, and brain lipid modifications with disease progression in tau P301S transgenic mice as a model of frontotemporal lobar degeneration-tau. J Neuropathol Exp Neurol 74:975–999CrossRefGoogle Scholar
- Piletz JE, Aricioglu F, Cheng JT, Fairbanks CA, Gilad VH, Haenisch B, Halaris A, Hong S, Lee JE, Li J, Liu P, Molderings GJ, Rodrigues AL, Satriano J, Seong GJ, Wilcox G, Wu N, Gilad GM (2013) Agmatine: clinical applications after 100 years in translation. Drug Discov Today 18:880–893CrossRefGoogle Scholar
- Reis DJ, Regunathan S (2000) Is agmatine a novel neurotransmitter in brain? Trends. Pharmacol Sci 21:187–193Google Scholar
- Sankaranarayanan S, Barten DM, Vana L, Devidze N, Yang L, Cadelina G, Hoque N, DeCarr L, Keenan S, Lin A, Cao Y, Snyder B, Zhang B, Nitla M, Hirschfeld G, Barrezueta N, Polson C, Wes P, Rangan VS, Cacace A, Albright CF, Meredith J Jr, Trojanowski JQ, Lee VM, Brunden KR, Ahlijanian M (2015) Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models. PLoS ONE 10(5):e0125614CrossRefGoogle Scholar
- Seiller N (2004) Catabolism of polyamines. Amino Acids 26:217–233Google Scholar
- Zhang B, Carroll J, Trojanowski JQ, Yao Y, Iba M, Potuzak JS, Hogan AM, Xie SX, Ballatore C, Smith AB 3rd, Lee VM, Brunden KR (2012) The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J Neurosci 32:3601–3611CrossRefGoogle Scholar
- Zolman JF (1993) Biostatistics: experimental design and statistical inference. Oxford University Press, OxfordGoogle Scholar