Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway
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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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The MAPK pathway mediated tau-induced microglial activation.
“In vitro study also revealed that MAPK pathway mediated tau-induced microglial activation.384,385”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [385]
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Hemonnot-Girard, A.-L. (2021) · theses.fr (ABES) · doi:10.70675/9c8a4775zd774z494ez9bbazf7566faefa8f
Chronic stress and glucocorticoid actions in brain plasticity and Tau pathology
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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
- Publisher
- Oxford University Press (OUP)
- 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
- bronze
- doi.org
- 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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