Date Published: April 01, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Phillip F. Giannopoulos, Jian Chiu, Domenico Praticò.
The 5‐lipoxygenase (5LO) 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 5LO 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 5LO 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.
Alzheimer’s disease (AD) is a chronic neurodegenerative condition with dementia affecting approximately 6%–8% all person aged >65. From a pathologic point of view, AD is characterized by the progressive accumulation of insoluble intra‐ and extracellular Aβ peptides and intracellular aggregates of highly phosphorylated microtubule‐associated protein tau (Giannopoulos & Praticò, 2015). Human tauopathies, which include among other diseases progressive supranuclear palsy, Pick’s disease, and corticobasal degeneration, are neurodegenerative conditions that share with AD the formation and progressive accumulation of neurofibrillary tangles, which result from the deposition of hyperphosphorylated tau protein (Arendt, Stieler & Holzer, 2016; Spillantini & Goedert, 2013). While their etiology remains unknown, consistent data have emerged in the literature linking neuroinflammatory pathways to the neurodegenerative processes characteristic in these diseases. However, what remains still to be fully established is the origin of these inflammatory reactions and whether they play a functional role or are just secondary events in their pathogenesis (Ishizawa & Dickson, 2001; Laurent et al., 2007).
The current study demonstrates that chronic pharmacologic blockade of 5LO enzymatic activity by zileuton in the central nervous system of a relevant transgenic mouse model of human tauopathy, the P301S mice, by preventing leukotriene formation reduces neuroinflammation and thus lowers tau phosphorylation, improves behavioral deficits, and ameliorates synaptic pathology. Taken together, these data add extra experimental support to the notion that this enzymatic pathway and its metabolic products play a direct role in the development of the entire tau pathological phenotype, and for this reason, it is a viable therapeutic target with true modifying‐disease potential for the treatment human tauopathies.
In summary, our study provides further experimental support for the active role that the leukotrienes pathway plays in the pathogenesis of a model of pure tauopathy, in which it directly influences tau phosphorylation levels and solubility, memory and learning, and synaptic integrity. These new findings represent the successful completion of the initial step for the preclinical evaluation and development of this class of drugs, the 5LO inhibitors, as a novel and potentially disease‐modifying agents for neurodegenerative diseases characterized by the accumulation of highly phosphorylated microtubule‐associated protein tau.
This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All experiments were approved by the Institutional Animal Care and Use Committee.
The authors have no conflicting financial interest to disclose.
PFG and DP designed the study. PFG and JC carried out the experiments, performed the measurement, and analyzed the data. PFG and DP drafted the manuscript. All authors read and approved the final manuscript.