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

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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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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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.

Corresponding author

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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Keywords

  • Tauopathy
  • cdk5 kinase pathway
  • Five-lipoxygenase
  • Leukotrienes
  • Neuroinflammation
  • Behavior