ArticleAlzheimer's research & therapy2016
Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology.
Article in Alzheimer's research & therapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers, 1 of them a synthesis that pooled it.
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Who cites it
71 citing papers in PubMed, 1 synthesis or guideline pooled it, 140 citations in OpenAlex.
- Effect of Acupuncture on the p38 Signaling Pathway in Several Nervous System Diseases: A Systematic Review.International journal of molecular sciences · 2020Pooled it
- A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease.Alzheimer's research & therapy · 2021Trial
- Repeated mild spinal cord contusions exacerbate tauopathy development in PS19 mice.Acta neuropathologica communications · 2026Article
- Specific inhibition of p38α MAPK dampens neuroinflammation during acute alcohol withdrawal in mouse BV2 microglial cell line and rat organotypic hippocampal slice cultures.Alcohol (Fayetteville, N.Y.) · 2026Article
- Targeting of kinases to treat neurodegenerative diseases.Pharmacological reviews · 2026Review
- Toxic mechanisms of amyloid oligomers and therapeutic strategies.Protein science : a publication of the Protein Society · 2026Review
- Procoagulant Extracellular Vesicles Increase Neuronal Tau expression, Metabolism and Processing Through Tissue Factor and Protease Activated Receptor 2.Cellular and molecular neurobiology · 2026Article
- Peripheral blood microarray-based transcriptomic and epigenetic analyses identify immune, inflammation, and metabolic dysregulation in Alzheimer's disease.NPJ dementia · 2026Article
- Leveraging targeted kinase degradation as a novel therapeutic strategy for Alzheimer's disease.RSC medicinal chemistry · 2025Review
- Alcohol addiction and Alzheimer's disease: a molecular collision course.Translational psychiatry · 2025Review
- Multi-targeted approach via apigenin-7-O-glucoside for therapeutic intervention of Tau phosphorylating kinases in Alzheimer's disease.3 Biotech · 2025Article
- Cellular and molecular mechanisms of pathological tau phosphorylation in traumatic brain injury: implications for chronic traumatic encephalopathy.Molecular neurodegeneration · 2025Review
- Targeting of phosphorylated tau at threonine 181 by a Qβ virus-like particle vaccine is safe, highly immunogenic, and reduces disease severity in mice and rhesus macaques.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Article
- Ellagic Acid: A Green Multi-Target Weapon That Reduces Oxidative Stress and Inflammation to Prevent and Improve the Condition of Alzheimer's Disease.International journal of molecular sciences · 2025Review
- Endosomal traffic disorders: a driving force behind neurodegenerative diseases.Translational neurodegeneration · 2024Review
- CD2AP deficiency aggravates Alzheimer's disease phenotypes and pathology through p38 MAPK activation.Translational neurodegeneration · 2024Article
- A small molecule p38α MAPK inhibitor, MW150, attenuates behavioral deficits and neuronal dysfunction in a mouse model of mixed amyloid and vascular pathologies.Brain, behavior, & immunity - health · 2024Article
- p38α Mitogen-Activated Protein Kinase-An Emerging Drug Target for the Treatment of Alzheimer's Disease.Molecules (Basel, Switzerland) · 2024Review
- Inflammatory signaling pathways in the treatment of Alzheimer's disease with inhibitors, natural products and metabolites (Review).International journal of molecular medicine · 2023Review
11 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 1 country.
Funding
Abstract
backgroundHyperphosphorylation 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.
methodWe 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.
resultsFirst, 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.
conclusionsTaken together, these studies support p38α MAPK as a valid therapeutic target for the treatment of tauopathies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.