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

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

doi:10.1186/s13195-016-0221-y

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.

Highlights

Hyperphosphorylation and aggregation of tau protein are the pathological hallmarks of Alzheimer’s disease and related tauopathies
MW181 and SB239063 treatment rescued inflammationinduced phosphorylation of tau, p38α p38 mitogen-activated protein kinase (MAPK), and Activating transcription factor 2 (ATF2) in primary neurons To assess the effects of two brain-permeable p38α MAPK inhibitors (MW181 and SB239063) on the inflammationinduced tau hyperphosphorylation, we pretreated primary cortical neurons either with vehicle (VEH/saline), SB239063, or MW181 for 30 min and stimulated the primary neurons with conditioned media (CM) derived from Cx3cr1–/– primary microglia (Fig. 1a–c)
MAPK-activated protein kinase 2 (MK2)–/– mice are resistant to LPS-induced tau phosphorylation and show reduced levels of total p38α MAPK We have demonstrated previously that intraperitoneal administration of LPS results in elevated tau phosphorylation within the brain and that mice deficient for tolllike receptor 4 (TLR4) or IL-1β receptor (IL-1R) are resistant to this LPS-induced tau phosphorylation [22]

Summary

Introduction

Hyperphosphorylation and aggregation of tau protein are the pathological hallmarks of Alzheimer’s disease and related tauopathies. Our previous studies have suggested that the PXXP motif of tau can interact with SH3 domains of the Src family kinases (such as Fyn and Src) [5,6,7], which in turn affect actin remodeling in growth cones [7]. These tau–fyn [8] and tau–actin [9] ( reviewed in [10]) interactions were demonstrated in earlier studies.

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