Proteopathic tau primes and activates interleukin-1β via myeloid-cell-specific MyD88- and NLRP3-ASC-inflammasome pathway
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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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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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Self-citationNLRP3 inflammasome in neurodegenerative disease
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Self-citationTau induces inflammasome activation and microgliosis through acetylating NLRP3
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Aβ and Tau Regulate Microglia Metabolism via Exosomes in Alzheimer’s Disease
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ASC specks exacerbate α‑synuclein pathology via amplifying NLRP3 inflammasome activities
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C9orf72 dipeptides activate the NLRP3 inflammasome
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Tau in Multiple Sclerosis: A Review of Therapeutic Potential
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The deubiquitinase OTULIN regulates tau expression and RNA metabolism in neurons
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Self-citationRole of Tau Protein Hyperphosphorylation in Diabetic Retinal Neurodegeneration
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Multifactorial glial responses and their contributions to Alzheimer's disease continuum
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Self-citationd -amino acids restrain macrophage IL-1β release through gasdermin D acetylation
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Decoding neuroinflammation: the critical role of NLRP3 inflammasome in Alzheimer’s disease
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Sánchez, K. E., Jiang, S., Desai, S. P., Thompson, J., Hobson, S., Rosenberg, G. A., & Bhaskar, K. (2024) · STAR Protocols · doi:10.1016/j.xpro.2024.102916 · Cited by 2 · see citing works
Self-citationInnate Immune Status of Glia Modulates Prion Propagation in Early Stage of Infection
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Saffarpour, S., Tehran, P. S., Rahimi, B., & Nasirinezhad, F. (2025) · Physiology & Behavior · doi:10.1016/j.physbeh.2025.114990 · Cited by 1 · see citing works
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Inflammasome and neurodegenerative diseases
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Self-citationDapsone is an anticatalysis for Alzheimer’s disease exacerbationPreprint
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Self-citationDapsone is an Anticatalysis for Alzheimer's Disease ExacerbationPreprint
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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
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 36
- Issue
- 12
- Pages
- 109720
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC8491766
- 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
- gold
- doi.org
- Licence
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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