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Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology
Nicole Maphis1, Shanya Jiang1, Guixiang Xu2
1Department of Molecular Genetics and Microbiology, MSC08 4660, 1 University of New Mexico, University of New Mexico, Albuquerque, NM, 87131, USA.
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.
Insights
A new drug, MW181, effectively inhibits p38α MAPK, reducing tau phosphorylation and improving cognitive function in mouse models of Alzheimer's disease and tauopathies.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Tau protein hyperphosphorylation and aggregation are key pathological features of Alzheimer's disease and tauopathies.
- Microglial activation drives tau pathology and cognitive decline through p38 mitogen-activated protein kinase (p38 MAPK) signaling.
Purpose of the Study:
- To investigate the therapeutic potential of MW181, a novel small molecule inhibitor of p38α MAPK, for treating tauopathies.
- To evaluate the effects of MW181 on tau phosphorylation, aggregation, and cognitive function in vitro and in a mouse model.
Main Methods:
- In vitro studies using primary cortical neurons to assess MW181's effect on inflammation-induced p38α MAPK activation and tau phosphorylation.
- In vivo studies using aged hTau mice treated with MW181 via oral gavage to evaluate its impact on p38α MAPK activation, tau phosphorylation, aggregation, and cognitive performance.
Main Results:
- MW181 effectively blocked p38α MAPK activation and tau phosphorylation at specific sites (AT8, AT180) in neurons and hTau mice.
- Oral administration of MW181 significantly reduced Sarkosyl-insoluble tau aggregates and improved working memory in aged hTau mice.
- MW181 treatment decreased downstream p38α MAPK substrates (pMK2, pATF2) and inflammatory markers (interferon-γ, interleukin-1β).
Conclusions:
- p38α MAPK is a viable therapeutic target for Alzheimer's disease and related tauopathies.
- MW181 demonstrates significant potential as an orally bioavailable drug for treating tauopathies by inhibiting p38α MAPK signaling.
