Pharmacologic Inhibition of 5-lipoxygenase Improves Memory, Rescues Synaptic Dysfunction, and Ameliorates Tau Pathology in a Transgenic Model of Tauopathy

Overview

Journal Biol Psychiatry

Publisher Elsevier

Specialty Psychiatry

Date 2015 Mar 25

PMID 25802082

Citations 26

Authors

Phillip F Giannopoulos

Jin Chu

Margaret Sperow

Jian-Guo Li

W Haung Yu

Lynn G Kirby

Mary Abood

Domenico Pratico

Affiliations

Soon will be listed here.

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.

Citing Articles

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

Giannopoulos P, Chiu J, Pratico D Mol Neurobiol. 2024; 61(12):11026-11027.

PMID: 39090354 DOI: 10.1007/s12035-024-04402-2.

Pharmacotherapies for the Treatment of Progressive Supranuclear Palsy: A Narrative Review.

Dunning E, Decourt B, Zawia N, Shill H, Sabbagh M Neurol Ther. 2024; 13(4):975-1013.

PMID: 38743312 PMC: 11263316. DOI: 10.1007/s40120-024-00614-9.

Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets.

Gao C, Jiang J, Tan Y, Chen S Signal Transduct Target Ther. 2023; 8(1):359.

PMID: 37735487 PMC: 10514343. DOI: 10.1038/s41392-023-01588-0.

Retraction Note to: Overexpression of 5-Lipoxygenase Worsens the Phenotype of a Mouse Model of Tauopathy.

Giannopoulos P, Pratico D Mol Neurobiol. 2023; 60(5):2970-2971.

PMID: 36823264 DOI: 10.1007/s12035-023-03283-1.

Mitochondria-targeted antioxidant SkQ1 inhibits leukotriene synthesis in human neutrophils.

Sudina G, Golenkina E, Prikhodko A, Kondratenko N, Gaponova T, Chernyak B Front Pharmacol. 2022; 13:1023517.

PMID: 36506526 PMC: 9729262. DOI: 10.3389/fphar.2022.1023517.

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