Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation
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Brain inflammation generally accompanies and accelerates neurodegeneration. Here we report a microglial mechanism in which polyglutamine binding protein 1 (PQBP1) senses extrinsic tau 3R/4R proteins by direct interaction and triggers an innate immune response by activating a cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway. Tamoxifen-inducible and microglia-specific depletion of PQBP1 in primary culture in vitro and mouse brain in vivo shows that PQBP1 is essential for sensing-tau to induce nuclear translocation of nuclear factor κB (NFκB), NFκB-dependent transcription of inflammation genes, brain inflammation in vivo, and eventually mouse cognitive impairment. Collectively, PQBP1 is an intracellular receptor in the cGAS-STING pathway not only for cDNA of human immunodeficiency virus (HIV) but also for the transmissible neurodegenerative disease protein tau. This study characterises a mechanism of brain inflammation that is common to virus infection and neurodegenerative disorders.
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Jin et al. reported that AD pathogenic protein tau can bind to PQBP1 and trigger inflammation in the CNS by activating the cGAS-STING pathway.
“Jin et al. reported an interesting finding that AD pathogenic protein tau can bind to polyglutamine binding protein 1 (PQBP1) and trigger inflammation in the CNS by activating cGAS-STING pathway.405”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [405]
Recent work from Gan's group suggests that the cGAS-STING pathway is robustly activated in brains of tau transgenic mice, consistent with previous work in primary microglia treated with tau aggregates.
“While it is currently unknown whether tau-induced retrotransposons form eccDNA, recent work from Gan's group (Udeochu et al. 2023) suggests that the cGAS-STING pathway is robustly activated in brains of tau transgenic mice, consistent with previous work in primary microglia treated with tau aggregates (Jin et al. 2021).”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Jin et al. 2021
Misfolded proteins and protein aggregates, including tau, Aβ, α-synuclein, mutant huntingtin, TDP-43, SOD1, and FUS induce microglial activation and neuroinflammation.
“Numerous studies have reported that misfolded proteins and protein aggregates, including tau,136–139 Aβ,138,140 α-synuclein,141–144 mutant huntingtin,145 TDP-43,132,146 superoxide dismutase 1 (SOD1),147–149 and fused in sarcoma (FUS)150 induce microglial activation and neuroinflammation.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [136]
Tau seeds taken up by microglia can activate microglia, further exacerbating tau propagation and pathology.
“In addition, several studies have shown that tau seeds taken up by microglia can activate microglia, further exacerbating tau propagation and pathology [186, 192, 193].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [192]
Microglia uptake exogenous monomeric tau via LRP1 and TREM2, and then induce NF-κB activation through LRP1/PQBP1/cGAS/STING and TREM2/ERK/PI3K pathways, ultimately triggering neuronal death.
“Jin et al. reported that microglia uptake exogenous monomeric tau in parallel via two surface receptors, LRP1 and TREM2, and then induce nuclear factor NF-κB activation in microglia through two different pathways, LRP1/polyglutamine binding protein 1 (PQBP1)/cyclic GMP–AMP synthase (cGAS)/Stimulator of interferon genes (STING) and TREM2/extracellular signal-regulated kinase (ERK)/Phosphoinositide”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [192]
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- Authors
- Jin, M., Shiwaku, H., Tanaka, H., Obita, T., Ohuchi, S., Yoshioka, Y., Jin, X., Kondo, K., Fujita, K., Homma, H., Nakajima, K., Mizuguchi, M., & Okazawa, H.
- Affiliations
- Tokyo Medical and Dental University (JP)
- University of Toyama (JP)
- Soka University (JP)
- Corresponding author
- Okazawa, Hitoshi
- ORCID
- Venue
- Nature Communications
- Published
- 2021-11-15
- Volume
- 12
- Issue
- 1
- Pages
- 6565-6565
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8592984
- OpenAlex
- W3214109787
- Cited by
- 223
- References
- 97
- Citations by year
- 2026: 43 · 2025: 49 · 2024: 66 · 2023: 37 · 2022: 28
- FWCI
- 13.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- MEXT | Japan Society for the Promotion of Science (16H02655, 19H01042)
- Ministry of Education, Culture, Sports, Science and Technology (22110001, 22110002)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- tau protein, microglia, PQBP1, cGAS-STING pathway, neuroinflammation, neurodegeneration, NF-κB, innate immune response, HIV, cognitive impairment, intracellular receptors
- MeSH terms
- STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Brain, DNA-Binding Proteins, Encephalitis, Female, HIV, Humans, Immunity, Innate, Male, Membrane Glycoproteins, Membrane Proteins, Mice, Inbred C57BL, Nucleotidyltransferases, Tamoxifen, NF-kappa B, Microglia, Mice, Knockout, Neurodegenerative Diseases, Mice
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