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

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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.

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References

  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 137:489–505

    Article  CAS  Google Scholar 

  2. Arendt T, Stieler JT, Holzer M (2016) Tau and tauopathies. Brain Res Bull 126:238–292

    Article  CAS  Google Scholar 

  3. Kovacs GG (2015) Neuropathology of tauopathies: principles and practice. Neuropathol Appl Neurobiol 41(1):3–23

    Article  CAS  Google Scholar 

  4. Spillantini MG, Goedert M (2013) Tau pathology and neurodegeneration. Lancet Neurol 12:609–622

    Article  CAS  Google Scholar 

  5. Ishizawa K, Dickson DW (2001) Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J Neuropathol Exp Neurol 60:647–657

    Article  CAS  Google Scholar 

  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 140:184–200

    Article  Google Scholar 

  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 78:693–701

    Article  CAS  Google Scholar 

  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):1–8

    Google Scholar 

  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):1288

    Google Scholar 

  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

    Article  Google Scholar 

  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 86:582–590

    Article  CAS  Google Scholar 

  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:e70991

    Article  CAS  Google Scholar 

  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):1813–1820

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 74:348–356

    Article  CAS  Google Scholar 

  16. Joshi Y, Chu J, Praticò D (2013) Knockout of 5lipoxygenase prevents dexamethasone-induced tau pathology in the 3xTg mice. Aging Cell 12(4):706–711

    Article  CAS  Google Scholar 

  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 21:719–727

    Article  CAS  Google Scholar 

  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 103:2256–22678

    Article  CAS  Google Scholar 

  19. Wang Y, Mandelkow E (2016) Tau in physiology and pathology. Nat Rev Neurosci 17:5–21

    Article  Google Scholar 

  20. Chiti F, Dobson CM (2017) Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annu Rev Biochem 86:27–68

    Article  CAS  Google Scholar 

  21. Li C, Götz J (2017) Tau-based therapies in neurodegeneration: opportunities and challenges. Nat Rev Drug Discov 16(12):863–883

    Article  CAS  Google Scholar 

  22. Braczynski AK, Schulz JB, Bach JP (2017) Vaccination strategies in tauopathies and synucleinopathies. J Neurochem 143(5):467–488

    Article  CAS  Google Scholar 

  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 12:1419–1428

    Article  CAS  Google Scholar 

  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):105–126

    Article  Google Scholar 

  25. Steinhilber D, Hofmann B (2014) Recent advances in the search for novel 5-lipoxygenase inhibitors. Basic Clin Pharmacol Toxicol 114(1):70–77

    Article  CAS  Google Scholar 

  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–S139

    Google Scholar 

  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 45:751–762

    Article  CAS  Google Scholar 

  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 325:30–38

    Article  CAS  Google Scholar 

  29. Bennett M, Gilroy DW (2016) Lipid mediators in inflammation. Microbiol Spectr 2016:4(6). https://doi.org/10.1128/microbiolspec.MCHD-0035-2016

    Article  Google Scholar 

  30. Giannopoulos PF, Joshi YB, Praticò D (2014) Novel lipid signaling pathways in Alzheimer disease pathogenesis. Biochem Pharmacol 88(4):560–564

    Article  CAS  Google Scholar 

  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):763–767

    Article  Google Scholar 

  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):123–128

    Article  Google Scholar 

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Funding

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.

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Authors and Affiliations

  1. Alzheimer’s Center at Temple, Lewis Katz School of Medicine, Scott Richards North Star Foundation Chair, Alzheimer’s Research, Temple University, 947, Medical Education and Research Building, 3500 North Broad Street, Philadelphia, PA, 19140, USA

    Phillip F. Giannopoulos, Jian Chiu & Domenico Praticò

Authors
  1. Phillip F. Giannopoulos
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  2. Jian Chiu
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  3. Domenico Praticò
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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.

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Correspondence to Domenico Praticò.

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The authors have no conflicting financial interest to disclose.

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Giannopoulos, P.F., Chiu, J. & Praticò, D. Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway. Mol Neurobiol 56, 1211–1220 (2019). https://doi.org/10.1007/s12035-018-1124-7

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  • DOI: https://doi.org/10.1007/s12035-018-1124-7

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