Journal Article

Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology

Watterson, D. Martin, Bhaskar, Kiran, Xu, Guixiang, Van Eldik, Linda J., Lamb, Bruce T., Jiang, Shanya, Maphis, Nicole, Kokiko-Cochran, Olga N., Roy, Saktimayee M.

2016

Overview

Background Hyperphosphorylation and aggregation of tau protein are the pathological hallmarks of Alzheimer’s disease and related tauopathies. We previously demonstrated that the microglial activation induces tau hyperphosphorylation and cognitive impairment via activation of p38 mitogen-activated protein kinase (p38 MAPK) in the hTau mouse model of tauopathy that was deficient for microglial fractalkine receptor CX3CR1. Method We report an isoform-selective, brain-permeable, and orally bioavailable small molecule inhibitor of p38α MAPK (MW181) and its effects on tau phosphorylation in vitro and in hTau mice. Results First, pretreatment of mouse primary cortical neurons with MW181 completely blocked inflammation-induced p38α MAPK activation and AT8 (pS199/pS202) site tau phosphorylation, with the maximum effect peaking at 60–90 min after stimulation. Second, treatment of old (~20 months of age) hTau mice with MW181 (1 mg/kg body weight; 14 days via oral gavage) significantly reduced p38α MAPK activation compared with vehicle-administered hTau mice. This also resulted in a significant reduction in AT180 (pT231) site tau phosphorylation and Sarkosyl-insoluble tau aggregates. Third, MW181 treatment significantly increased synaptophysin protein expression and resulted in improved working memory. Fourth, MW181 administration reduced phosphorylated MAPK-activated protein kinase 2 (pMK2) and phosphorylated activating transcription factor 2 (pATF2), which are known substrates of p38α MAPK. Finally, MW181 reduced the expression of interferon-γ and interleukin-1β. Conclusions Taken together, these studies support p38α MAPK as a valid therapeutic target for the treatment of tauopathies.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Activating Transcription Factor 2 - drug effects / Alzheimer's disease / Analysis / Animals / Behavior, Animal / Biomedical and Life Sciences / Biomedicine / Care and treatment / Cerebral Cortex - drug effects / Diagnosis / Disease Models, Animal / Geriatric Psychiatry / Geriatrics/Gerontology / Interferon-gamma - drug effects / Interleukin-1beta - drug effects / Intracellular Signaling Peptides and Proteins - drug effects / Memory, Short-Term - drug effects / Mice / Mice, Inbred C57BL / Mice, Knockout / Microglia - drug effects / Neurology / Neurons / Neurons - drug effects / Neurosciences / p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors / p38 Mitogen-Activated Protein Kinases - drug effects / Protein Kinase Inhibitors - administration & dosage / Protein Kinase Inhibitors - pharmacology / Protein kinases / Protein-Serine-Threonine Kinases - drug effects / Pyridazines - administration & dosage / Pyridazines - pharmacology / Pyridines - administration & dosage / Pyridines - pharmacology / tau Proteins - drug effects / tau Proteins - metabolism / Tauopathies - drug therapy