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Pharmacologic blockade of 12/15-lipoxygenase ameliorates memory deficits, Aβ and tau neuropathology in the triple-transgenic mice

Molecular Psychiatry volume 20, pages 1329–1338 (2015)Cite this article

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Abstract

The 12/15-lipoxygenase (12/15LO) enzyme is widely distributed within the central nervous system. Previous work showed that this protein is upregulated in Alzheimer’s disease (AD), and plays an active role in the development of brain amyloidosis in amyloid beta (Aβ)-precursor protein transgenic mice (Tg2576). In the present paper, we studied the effect of its pharmacologic inhibition on the AD-like phenotype of a mouse model with plaques and tangles, the triple-transgenic mice. Compared with mice receiving placebo, the group treated with PD146176, a specific 12/15LO inhibitor, manifested a significant improvement of their memory deficits. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a decrease in the β-secretase pathway. In addition, while total tau-soluble levels were unchanged for both groups, PD146176-treated mice had a significant reduction in its phosphorylation state and insoluble fraction, which specifically associated with decrease in stress-activated protein kinase/c-Jun N-terminal kinase activity. In vitro study showed that the effect on tau and Aβ were independent from each other. These data establish a functional role for 12/15LO in the pathogenesis of the full spectrum of the AD-like phenotype and represent the successful completion of the initial step for the preclinical development of 12/15LO inhibitors as novel therapeutic agents for AD.

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Acknowledgements

This work was in part supported by a grant from the Alzheimer’s Art Quilt Initiative. We would like to thank Dr Peter Davis for the generous gift of the PHF-1 antibody used in the study.

Author Contributions

JC and DP designed the study, developed the experimental design, performed data analysis and wrote the paper. JC, J-GL, PFG and BEB performed the experiment. BEB, WC and MA-G were involved in the synthesis of PD146176 and assessment of pharmacological effect on the enzyme activity. All the authors discussed the results and commented on the manuscript.

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Authors and Affiliations

  1. Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA

    J Chu, J-G Li, P F Giannopoulos & D Praticò

  2. Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA, USA

    B E Blass, W Childers & M Abou-Gharbia

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  1. J Chu
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  2. J-G Li
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  7. D Praticò
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Correspondence to D Praticò.

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Chu, J., Li, JG., Giannopoulos, P. et al. Pharmacologic blockade of 12/15-lipoxygenase ameliorates memory deficits, Aβ and tau neuropathology in the triple-transgenic mice. Mol Psychiatry 20, 1329–1338 (2015). https://doi.org/10.1038/mp.2014.170

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