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.

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Published in Alzheimer's Research & Therapy, v. 8, 54, p. 1-15.

© The Author(s). 2016

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Funding Information

This work was supported primarily by the Bright Focus Foundation Pilot Award (AHAF0311KB) and other funding: UNM BRaIN CoBRE P30 Pilot and UNM SOM RAC Awards, Alzheimer’s Association (NIRG-11-204995), NIH/NINDS (R21 NS077089 and R01 NS083704) funding to KB, Alzheimer’s Association (MCPG to BTL) and DOD (ERMS#12109018 to BTL), and NIH (AG023012 to BTL; NS074804 to BTL; R01 NS093920 to LJVE).

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