title: Misfolded truncated protein τ induces innate immune response via MAPK pathway.
abstract: Neuroinflammation plays a key role in the pathogenesis of Alzheimer's disease and related tauopathies. We have previously shown that expression of nonmutated human truncated τ (151-391, 4R), derived from sporadic Alzheimer's disease, induced neurofibrillary degeneration accompanied by microglial and astroglial activation in the brain of transgenic rats. The aim of the current study was to determine the molecular mechanism underlying innate immune response induced by misfolded truncated τ. We found that purified recombinant truncated τ induced morphological transformation of microglia from resting into the reactive phenotype. Simultaneously, truncated τ caused the release of NO, proinflammatory cytokines (IL-1β, IL-6, TNF-α), and tissue inhibitor of metalloproteinase-1 from the mixed glial cultures. Notably, when the pure microglial culture was activated with truncated τ, it displayed significantly higher levels of the proinflammatory cytokines, suggesting a key role of microglia in the τ-mediated inflammatory response. Molecular analysis showed that truncated τ increased the mRNA levels of three MAPKs (JNK, ERK1, p38β) and transcription factors AP-1 and NF-κB that ultimately resulted in enhanced mRNA expression of IL-1β, IL-6, TNF-α, and NO. Our results showed for the first time, to our knowledge, that misfolded truncated protein τ is able to induce innate immune response via a MAPK pathway. Consequently, we suggest that misfolded truncated protein τ represents a viable target for immunotherapy of Alzheimer's disease.
authors.affiliation: Institute of Neuroimmunology, Slovak Academy of Sciences, Center of Excellence for Alzheimer's Disease and Related Disorders, 845 10 Bratislava, Slovak Republic.
authors.forename: Andrej
authors.initials: A
authors.lastname: Kovac
authors.forename: Norbert
authors.initials: N
authors.lastname: Zilka
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Kazmerova
authors.forename: Martin
authors.initials: M
authors.lastname: Cente
authors.forename: Monika
authors.initials: M
authors.lastname: Zilkova
authors.forename: Michal
authors.initials: M
authors.lastname: Novak
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007113:Immunity, Innate; D007150:Immunohistochemistry; D017628:Microglia / Q000276:immunology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000276:immunology*; D051381:Rats; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D016875:tau Proteins / Q000276:immunology*
chemical_list: D016207:Cytokines; D011994:Recombinant Proteins; D016875:tau Proteins; D020929:Mitogen-Activated Protein Kinase Kinases