Cited by 80Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsInflammasome and immune disorders

Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway

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Kovac, Andrej, Zilka, Norbert, Kazmerova, Zuzana, Cente, Martin, Zilkova, Monika, Novak, Michal·2011·The Journal of Immunology

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.

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Authors
Kovac, A., Zilka, N., Kazmerova, Z., Cente, M., Zilkova, M., & Novak, M.
Affiliations
  • Institute of Neuroimmunology, Slovak Academy of Sciences, Center of Excellence for Alzheimer’s Disease and Related Disorders , 845 10 Bratislava ,
  • Slovak Academy of Sciences (SK)
Corresponding author
  • Kazmerova, Zuzana
  • Cente, Martin
Venue
The Journal of Immunology
Published
2011-09-01
Volume
187
Issue
5
Pages
2732-2739
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
OpenAlex
W2167163936
Cited by
75
References
85
Citations by year
2025: 6 · 2024: 8 · 2023: 8 · 2022: 5 · 2021: 11 · 2020: 6 · 2019: 10 · 2018: 8 · 2017: 2 · 2016: 1 · 2015: 4 · 2014: 3 · 2013: 1 · 2012: 2
FWCI
1.31
Type
journal article
Language
en
Open access
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Agentúra na Podporu Výskumu a Vývoja (APVV-0631-07, APVV-0603-06)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
tauopathy, Alzheimer's disease, neuroinflammation, innate immune response, microglial activation, MAPK signaling, JNK, ERK1, p38 MAPK, NF-κB, AP-1, inflammatory cytokines, nitric oxide, TIMP-1, immunotherapy targets
MeSH terms
Animals, Enzyme-Linked Immunosorbent Assay, Humans, Immunity, Innate, Immunohistochemistry, Recombinant Proteins, Signal Transduction, Cytokines, tau Proteins, Microglia, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Reverse Transcriptase Polymerase Chain Reaction, Mitogen-Activated Protein Kinase Kinases, Rats

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