title: Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Taken together, these studies support p38α MAPK as a valid therapeutic target for the treatment of tauopathies.
authors.affiliation: Department of Molecular Genetics and Microbiology, MSC08 4660, 1 University of New Mexico, University of New Mexico, Albuquerque, NM, 87131, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Maphis
authors.affiliation: Department of Molecular Genetics and Microbiology, MSC08 4660, 1 University of New Mexico, University of New Mexico, Albuquerque, NM, 87131, USA.
authors.forename: Shanya
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Stark Neurosciences Research Institute, Indiana University, 320W 15th Street, NB Suite 414C, Indianapolis, IN, 46202, USA.
authors.forename: Guixiang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Neurosciences, The Ohio State University, 4198 Graves Hall, 333 West 10th Avenue, Columbus, OH, 43210, USA.
authors.forename: Olga N
authors.initials: ON
authors.lastname: Kokiko-Cochran
authors.affiliation: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Ward Building Room Mail Code W896, 303 E Chicago Avenue, Chicago, IL, 60611, USA.
authors.forename: Saktimayee M
authors.initials: SM
authors.lastname: Roy
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, 101 Sanders-Brown Bldg., 800S. Limestone Street, Lexington, KY, 40536, USA.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Van Eldik
authors.affiliation: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Ward Building Room Mail Code W896, 303 E Chicago Avenue, Chicago, IL, 60611, USA.
authors.forename: D Martin
authors.initials: DM
authors.lastname: Watterson
authors.affiliation: Stark Neurosciences Research Institute, Indiana University, 320W 15th Street, NB Suite 414C, Indianapolis, IN, 46202, USA.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Lamb
authors.affiliation: Department of Molecular Genetics and Microbiology, MSC08 4660, 1 University of New Mexico, University of New Mexico, Albuquerque, NM, 87131, USA. KBhaskar@salud.unm.edu.
authors.forename: Kiran
authors.identifier: 0000-0001-6064-8106
authors.initials: K
authors.lastname: Bhaskar
mesh_terms: D051698:Activating Transcription Factor 2 / Q000187:drug effects*; D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000187:drug effects; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000187:drug effects*; D053583:Interleukin-1beta / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects*; D008570:Memory, Short-Term / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects*; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D024801:Tauopathies / Q000188:drug therapy*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects*; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D051698:Activating Transcription Factor 2; D007371:Interferon-gamma; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011724:Pyridazines; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; D016875:tau Proteins; D000099190:MAP-Kinase-Activated Kinase 2; C497106:Atf2 protein, mouse; C558298:Mapt protein, mouse; C000597455:N,N-dimethyl-6-(naphthalen-1-yl)-5-(pyridin-4-yl)pyridazin-3-amine
keywords: Alzheimer’s disease; MW01-10-181SRM; MW181 and MK2 deficiency; SB239063; hTau; p38 MAPK inhibitor; p38 mitogen activated protein kinase; tau; tauopathies