Advertisement

Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway

  • Phillip F. Giannopoulos
  • Jian Chiu
  • Domenico Praticò
Article

Abstract

Previous studies showed that the leukotrienes pathway is increased in human tauopathy and that its manipulation may modulate the onset and development of the pathological phenotype of tau transgenic mice. However, whether interfering with leukotrienes biosynthesis is beneficial after the behavioral deficits and the neuropathology have fully developed in these mice is not known. To test this hypothesis, aged tau transgenic mice were randomized to receive zileuton, a specific leukotriene biosynthesis inhibitor, or vehicle starting at 12 months of age for 16 weeks and then assessed in their functional and pathological phenotype. Compared with baseline, we observed that untreated tau mice had a worsening of their memory and spatial learning. By contrast, tau mice treated with zileuton had a reversal of these deficits and behaved in an undistinguishable manner from wild-type mice. Leukotriene-inhibited tau mice had an amelioration of synaptic integrity, lower levels of neuroinflammation, and a significant reduction in tau phosphorylation and pathology, which was secondary to an involvement of the cdk5 kinase pathway. Taken together, our findings represent the first demonstration that the leukotriene biosynthesis is functionally involved at the later stages of the tau pathological phenotype and represents an ideal target with viable therapeutic potential for treating human tauopathies.

Keywords

Tauopathy cdk5 kinase pathway Five-lipoxygenase Leukotrienes Neuroinflammation Behavior 

Notes

Authors’ Contributions

PFG and DP designed the study; PFG and JC performed the experiments; PFG and DP analyzed the data and drafted the manuscript. All authors have discussed the results and seen the final version of the paper before submission.

Funding Information

Domenico Praticò is the Scott Richards North Star Foundation Chair of Alzheimer’s research. This study was supported in part by grants from The Wanda Simone Endowment for Neuroscience and the Scott Richards North Star Charitable Foundation.

Compliance with Ethical Standards

Conflict of Interest

The authors have no conflicting financial interest to disclose.

References

  1. 1.
    Yerbury JJ, Ooi L, Dillin A, Saunders DN, Hatters DM, Berat PM, Cashman NR, Wilson MR et al (2016) Walking the tightrope: proteostasis and neurodegenerative diseases. J Neurochem 137:489–505CrossRefPubMedGoogle Scholar
  2. 2.
    Arendt T, Stieler JT, Holzer M (2016) Tau and tauopathies. Brain Res Bull 126:238–292CrossRefPubMedGoogle Scholar
  3. 3.
    Kovacs GG (2015) Neuropathology of tauopathies: principles and practice. Neuropathol Appl Neurobiol 41(1):3–23CrossRefPubMedGoogle Scholar
  4. 4.
    Spillantini MG, Goedert M (2013) Tau pathology and neurodegeneration. Lancet Neurol 12:609–622CrossRefPubMedGoogle Scholar
  5. 5.
    Ishizawa K, Dickson DW (2001) Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J Neuropathol Exp Neurol 60:647–657CrossRefPubMedGoogle Scholar
  6. 6.
    Laurent C, Dorothee G, Hunot S, Martin E, Monnet Y, Duchamp M, Dong Y, Légeron FP et al (2007) Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy. Brain 140:184–200CrossRefGoogle Scholar
  7. 7.
    Giannopoulos PF, Chu J, Sperow N, Li JG, Yu WH, Kirby LG, Abood M, Praticò D (2015) Pharmacologic inhibition of 5-lipoxygenase improves memory, rescues synaptic dysfunction, and ameliorates tau pathology in a transgenic model of tauopathy. Biol Psychiatry 78:693–701CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Joshi Y, Praticò D (2015) The 5-lipoxygenase pathway: oxidative and inflammatory contributions to the Alzheimer’s disease pathogenesis. Front Cell Neurosci 8(436):1–8Google Scholar
  9. 9.
    Vagnozzi AN, Giannopoulos PF, Praticò D (2017) The direct role of 5-lipoxygenase on tau pathology, synaptic integrity and cognition in a mouse model of tauopathy. Transl. Psychiatry 7(12):1288Google Scholar
  10. 10.
    Giannopoulos PF, Praticò D (2017) Overexpression of 5-lipoxygenase worsens the phenotype of a mouse model of tauopathy. Mol Neurobiol.  https://doi.org/10.1007/s12035-017-0817-7
  11. 11.
    Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P (2003) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86:582–590CrossRefPubMedGoogle Scholar
  12. 12.
    Chu J, Li JG, Praticò D (2013) Zileuton improves memory deficits, amyloid and tau pathology in a mouse model of Alzheimer’s disease with plaques and tangles. PLoS One 8:e70991CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Di Meco A, Joshi YB, Praticò D (2014) Sleep deprivation impairs memory, tau metabolism, and synaptic integrity of a mouse model of Alzheimer’s disease with plaques and tangles. Neurobiol Aging 35(8):1813–1820CrossRefPubMedGoogle Scholar
  14. 14.
    Li JG, Barrero C, Merali S, Praticò D (2017) Five lipoxygenase hypomethylation mediates the homocysteine effect on Alzheimer’s phenotype. Sci Rep 7:46002.  https://doi.org/10.1038/srep46002. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Giannopoulos PF, Chu J, Joshi YB, Sperow M, Li JG, Kirby LG, Praticò D (2013) Five-lipoxygenase activating protein reduction ameliorates cognitive deficit, synaptic dysfunction, and neuropathology in a mouse model of Alzheimer’s disease. Biol Psychiatry 74:348–356CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Joshi Y, Chu J, Praticò D (2013) Knockout of 5lipoxygenase prevents dexamethasone-induced tau pathology in the 3xTg mice. Aging Cell 12(4):706–711CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Weaver CL, Espinoza M, Kress Y, Davies P (2000) Conformational change as one of the earliest alterations of tau in Alzheimer’s disease. Neurobiol Aging 21:719–727CrossRefPubMedGoogle Scholar
  18. 18.
    Kelleher I, Garwood C, Hanger DP, Anderton BH, Noble W (2007) Kinase activities increase during the development of tauopathy in htau mice. J Neurochem 103:2256–22678CrossRefPubMedGoogle Scholar
  19. 19.
    Wang Y, Mandelkow E (2016) Tau in physiology and pathology. Nat Rev Neurosci 17:5–21CrossRefPubMedGoogle Scholar
  20. 20.
    Chiti F, Dobson CM (2017) Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annu Rev Biochem 86:27–68CrossRefPubMedGoogle Scholar
  21. 21.
    Li C, Götz J (2017) Tau-based therapies in neurodegeneration: opportunities and challenges. Nat Rev Drug Discov 16(12):863–883CrossRefPubMedGoogle Scholar
  22. 22.
    Braczynski AK, Schulz JB, Bach JP (2017) Vaccination strategies in tauopathies and synucleinopathies. J Neurochem 143(5):467–488CrossRefPubMedGoogle Scholar
  23. 23.
    Wahl D, Coogan SC, Solon-Biet SM, de Cabo R, Haran JB, Raubenheimer D, Cogger VC, Mattson MP et al (2017) Cognitive and behavioral evaluation of nutritional interventions in rodent models of brain aging and dementia. Clin Interv Aging 12:1419–1428CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Stewart S, Cacucci F, Lever C (2011) Which memory task for my mouse? A systematic review of spatial memory performance in the Tg2576 Alzheimer’s mouse model. J Alzheimers Dis 26(1):105–126CrossRefPubMedGoogle Scholar
  25. 25.
    Steinhilber D, Hofmann B (2014) Recent advances in the search for novel 5-lipoxygenase inhibitors. Basic Clin Pharmacol Toxicol 114(1):70–77CrossRefPubMedGoogle Scholar
  26. 26.
    Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K (2013) Abnormal hyperphosphorylation of tau: sites, regulation and molecular mechanism of neurofibrillary degeneration. J Alz Dis 33(suppl.1):S123–S139Google Scholar
  27. 27.
    Alldred MJ, Duff KE, Ginsberg SD (2012) Microarray analysis of CA1 pyramidal neurons in a mouse model of tauopathy reveals progressive synaptic dysfunction. Neurobiol Dis 45:751–762CrossRefPubMedGoogle Scholar
  28. 28.
    Moreno H, Morfini G, Buitrago L, Ujlaki G, Choi S, Yu E, Moreira JE, Avila J et al (2016) Tau pathology-mediated presynaptic dysfunction. Neuroscience 325:30–38CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Bennett M, Gilroy DW (2016) Lipid mediators in inflammation. Microbiol Spectr 2016:4(6).  https://doi.org/10.1128/microbiolspec.MCHD-0035-2016 Google Scholar
  30. 30.
    Giannopoulos PF, Joshi YB, Praticò D (2014) Novel lipid signaling pathways in Alzheimer disease pathogenesis. Biochem Pharmacol 88(4):560–564CrossRefPubMedGoogle Scholar
  31. 31.
    Chen MH, Li CT, Tsai CF, Lin WC, Chang WH, Chen TJ, Pan TJ, Su TL et al (2014) Risk of dementia among patients with asthma: a nationwide longitudinal study. J Am Med Dir Assoc 15(10):763–767CrossRefPubMedGoogle Scholar
  32. 32.
    Peng YH, Wu BR, Liao WC, Muo WC, Hsia TC, Kao CH (2015) Adult asthma increases dementia risk: a nationwide cohort study. J Epidemiol Comm Health 69(2):123–128CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Alzheimer’s Center at Temple, Lewis Katz School of Medicine, Scott Richards North Star Foundation Chair, Alzheimer’s ResearchTemple UniversityPhiladelphiaUSA

Personalised recommendations