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Biol Psychiatry. 2015 Nov 15;78(10):693-701. doi: 10.1016/j.biopsych.2015.01.015. Epub 2015 Feb 7.

Pharmacologic inhibition of 5-lipoxygenase improves memory, rescues synaptic dysfunction, and ameliorates tau pathology in a transgenic model of tauopathy.

Author information

1
Center for Translational Medicine; Department of Pharmacology.
2
Center for Substance Abuse Research.
3
Taub Institute for Alzheimer's Disease Research, Department of Pathology and Cell Biology, Columbia University, New York, New York.
4
Center for Substance Abuse Research; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
5
Center for Translational Medicine; Department of Pharmacology. Electronic address: praticod@temple.edu.

Abstract

BACKGROUND:

5-Lipoxygenase (5-LO) is a protein widely distributed in the central nervous system where it modulates amyloidosis and memory impairments in transgenic mouse models of Alzheimer's disease. However, no data are available as to whether 5-LO is elevated in human tauopathy or if it directly influences tau pathology in a relevant model of the disease.

METHODS:

We assayed 5-LO levels in brain samples from patients with tauopathy and transgenic tau mice, and we evaluated the effect of 5-LO pharmacologic inhibition on the phenotype of these mice.

RESULTS:

The 5-LO protein is upregulated in human tauopathy and transgenic tau mice brains. Pharmacologic blockade of 5-LO in tau mice resulted in significant memory improvement, rescue of synaptic integrity and dysfunction, and reduction of tau pathology via a cdk5-dependent mechanism.

CONCLUSIONS:

These results establish a key role of 5-LO in the development of the tau pathology phenotype and demonstrate it to be a novel viable therapeutic target for the pharmacologic treatment of human tauopathy.

KEYWORDS:

5-Lipoxygenase; Behavior; Frontotemporal dementia; Synapse; Tau protein; Tauopathy; Transgenic tau mice

PMID:
25802082
PMCID:
PMC4529386
DOI:
10.1016/j.biopsych.2015.01.015
[Indexed for MEDLINE]
Free PMC Article

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