Open AccessAntileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice
Author(s) -
Giannopoulos Phillip F.,
Chiu Jian,
Praticò Domenico
Publication year - 2018
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12759
Subject(s) - tauopathy , neuropathology , genetically modified mouse , downregulation and upregulation , phosphorylation , neuroscience , transgene , biology , blockade , pharmacology , microbiology and biotechnology , neurodegeneration , medicine , disease , pathology , biochemistry , receptor , gene
Summary The 5‐lipoxygenase (5 LO ) is a source of inflammatory leukotrienes and is upregulated in Alzheimer's disease and related tauopathies. However, whether it directly modulates tau phosphorylation and the development of its typical neuropathology in the absence of Aβ or is a secondary event during the course of the disease pathogenesis remains to be fully elucidated. The goal of this study was to evaluate the effect that pharmacologic blockade of this inflammatory pathway has on the phenotype of a transgenic mouse model of tauopathy, the P301S mice. Starting at 3 months of age, P301S mice were randomized to receive zileuton, a specific 5 LO blocker, for 7 months; then, its effect on their behavioral deficits and neuropathology was assessed. Inhibition of leukotrienes formation was associated with a reduction in tau phosphorylation and an amelioration of memory and learning as well as synaptic integrity, which were secondary to a downregulation of the cdk5 kinase pathway. Our results demonstrate that the 5 LO enzyme is a key player in modulating tau phosphorylation and pathology and that blockade of its enzymatic activity represents a desirable disease‐modifying therapeutic approach for tauopathy.