Cited by 92Alzheimer's disease research and treatmentsInflammasome and immune disordersNeuroinflammation and Neurodegeneration Mechanisms

Proteopathic tau primes and activates interleukin-1β via myeloid-cell-specific MyD88- and NLRP3-ASC-inflammasome pathway

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Jiang, Shanya, Maphis, Nicole M., Binder, Jessica, Chisholm, Devon, Weston, Lea, Duran, Walter, Peterson, Crina, Zimmerman, Amber +10 more·2021·Cell Reports

Abstract

Pathological hyperphosphorylation and aggregation of tau (pTau) and neuroinflammation, driven by interleukin-1β (IL-1β), are the major hallmarks of tauopathies. Here, we show that pTau primes and activates IL-1β. First, RNA-sequence analysis suggests paired-helical filaments (PHFs) from human tauopathy brain primes nuclear factor κB (NF-κB), chemokine, and IL-1β signaling clusters in human primary microglia. Treating microglia with pTau-containing neuronal media, exosomes, or PHFs causes IL-1β activation, which is NLRP3, ASC, and caspase-1 dependent. Suppression of pTau or ASC reduces tau pathology and inflammasome activation in rTg4510 and hTau mice, respectively. Although the deletion of MyD88 prevents both IL-1β expression and activation in the hTau mouse model of tauopathy, ASC deficiency in myeloid cells reduces pTau-induced IL-1β activation and improves cognitive function in hTau mice. Finally, pTau burden co-exists with elevated IL-1β and ASC in autopsy brains of human tauopathies. Together, our results suggest pTau activates IL-1β via MyD88- and NLRP3-ASC-dependent pathways in myeloid cells, including microglia.

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Crossref · 10.1016/j.celrep.2021.109720

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  • Mitochondrial abnormalities, synaptic loss and dysfunction, altered axonal transport, and activation of cell death pathways have been implicated as consequences of tau mislocalization or oligomerization.

    “Mitochondrial abnormalities, synaptic loss and dysfunction, altered axonal transport, and activation of cell death pathways (including caspase activation and inflammatory responses) have all been directly or indirectly implicated as consequences of tau mislocalization or oligomerization (20, 40, 43–52).”

    From All the Tau We Cannot See (2023) · cites this paper as [45]

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Authors
Jiang, S., Maphis, N. M., Binder, J., Chisholm, D., Weston, L., Duran, W., Peterson, C., Zimmerman, A., Mandell, M. A., Jett, S. D., Bigio, E., Geula, C., Mellios, N., Weick, J. P., Rosenberg, G. A., Latz, E., Heneka, M. T., & Bhaskar, K.
Affiliations
  • University of New Mexico (US)
  • Northwestern University (US)
  • University of Bonn (DE)
Corresponding author
Bhaskar, Kiran
Venue
Cell Reports
Publisher
Elsevier BV
Published
2021-09
Volume
36
Issue
12
Pages
109720
ISSN
2211-1247 (ISSN-L)
OpenAlex
W3199317951
Cited by
92
References
85
Citations by year
2026: 15 · 2025: 22 · 2024: 17 · 2023: 25 · 2022: 13
FWCI
8.63
Type
journal article
Language
en
Open access
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, other-oa)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Genentech
  • National Institutes of Health (RF1NS083704-05A1, R01NS116051, R21NS077089, P20GM121176-04, R21NS093442)
  • National Institute on Aging
  • Université de Lausanne
  • University of New Mexico
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
tauopathy, tau hyperphosphorylation, IL-1β, MyD88, NLRP3 inflammasome, ASC, caspase-1, microglia, neuroinflammation, paired helical filaments, exosomes, NF-κB signaling, myeloid cells, cognitive function, rTg4510 mice
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Cells, Cultured, Disease Models, Animal, Doxorubicin, Humans, Mice, Inbred C57BL, Signal Transduction, Down-Regulation, NF-kappa B, tau Proteins, Microglia, Caspase 1, Myeloid Cells, Tauopathies, Mice, CARD Signaling Adaptor Proteins, Interleukin-1beta, Myeloid Differentiation Factor 88, Inflammasomes

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