Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway

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 tau (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 tau. We found that purified recombinant truncated tau induced morphological transformation of microglia from resting into the reactive phenotype. Simultaneously, truncated tau caused the release of NO, proinflammatory cytokines (IL-1 beta, IL-6, TNF-alpha), and tissue inhibitor of metalloproteinase-1 from the mixed glial cultures. Notably, when the pure microglial culture was activated with truncated tau, it displayed significantly higher levels of the proinflammatory cytokines, suggesting a key role of microglia in the t-mediated inflammatory response. Molecular analysis showed that truncated tau increased the mRNA levels of three MAPKs (JNK, ERK1, p38 beta) and transcription factors AP-1 and NF-kappa B that ultimately resulted in enhanced mRNA expression of IL-1 beta, IL-6, TNF-alpha, and NO. Our results showed for the first time, to our knowledge, that misfolded truncated protein tau is able to induce innate immune response via a MAPK pathway. Consequently, we suggest that misfolded truncated protein tau represents a viable target for immunotherapy of Alzheimer's disease. The Journal of Immunology, 2011, 187: 2732-2739.