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Cited by 609Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy

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Chen, Xiaoying, Firulyova, Maria, Manis, Melissa, Herz, Jasmin, Smirnov, Igor, Aladyeva, Ekaterina, Wang, Chanung, Bao, Xin +9 more·2023·Nature
DOI 10.1038/s41586-023-05788-0PMC PMC10258627
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Abstract

Extracellular deposition of amyloid-β as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks of Alzheimer's disease 1,2. The regional progression of brain atrophy in Alzheimer's disease highly correlates with tau accumulation but not amyloid deposition 3-5, and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. So far, little is known about the extent or role of the adaptive immune response and its interaction with the innate immune response in the presence of amyloid-β or tau pathology 6. Here we systematically compared the immunological milieux in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not those with amyloid deposition developed a unique innate and adaptive immune response and that depletion of microglia or T cells blocked tau-mediated neurodegeneration. Numbers of T cells, especially those of cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the Alzheimer's disease brain. T cell numbers correlated with the extent of neuronal loss, and the cells dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of interferon-γ and PDCD1 signalling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy- and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in Alzheimer's disease and primary tauopathies.

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  • APOE4 exacerbates tau-induced neurodegeneration, partially attributed to a critical immune hub that involves IFN-driven microglial activation and interaction with cytotoxic T cells.

    “Moreover, APOE4 exacerbates tau-induced neurodegeneration, partially attributed to a critical immune hub that involves IFN-driven microglial activation and interaction with cytotoxic T cells64,65.”

    From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [65]

    The paper reports somewhat greater brain atrophy in tauopathy mice expressing APOE4 than in those expressing APOE3, and its ‘Interaction of microglia and T cells’ section links tauopathy to interferon-activated microglia and T-cell infiltration. But the ‘Increased T cells with tau pathology’ section says T-cell increases also occur with APOE3 and mouse ApoE; the paper does not establish that this immune hub specifically explains APOE4’s additional effect. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • APOE4 greatly exacerbates tau-induced neurodegeneration, partially attributed to a critical immune hub involving IFN-driven microglial activation and interaction with cytotoxic T cells.

    “Moreover, APOE4 greatly exacerbates tau-induced neurodegeneration, partially attributed to a critical immune hub that involves IFN-driven microglial activation and interaction with cytotoxic T cells60,61.”

    From <i>APOE3</i> - <i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [61]

    The Abstract (page not provided) reports prominent atrophy in tauopathy mice expressing either APOE3 or APOE4, with only 'somewhat greater' atrophy in the APOE4 mice; it does not support 'greatly exacerbates' relative to APOE3. The Abstract and 'Interaction of microglia and T cells' section (pages not provided) support the described immune hub involving IFN-activated microglia and cytotoxic T cells. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • A prior investigation highlighted the higher inflammatory reactivity (i.e., microglial MHC II + proteins and T cells) associated with tau-induced neurodegeneration, but not those with amyloid deposition.

    “A prior investigation highlighted the higher inflammatory reactivity (i.e., microglial MHC II + proteins and T cells) associated with tau-induced neurodegeneration, but not those with amyloid deposition [88].”

    From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [88]

  • Apoe deletion rescued brain atrophy and altered microglia and T cells, tying together the role of APOE and the innate and adaptive immune responses to tau vs. plaques via microglia.

    “Moreover, Apoe deletion rescued brain atrophy and altered microglia and T cells, tying together the role of APOE and the innate and adaptive immune responses to tau vs. plaques via microglia [88].”

    From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [88]

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Authors
Chen, X., Firulyova, M., Manis, M., Herz, J., Smirnov, I., Aladyeva, E., Wang, C., Bao, X., Finn, M. B., Hu, H., Shchukina, I., Kim, M. W., Yuede, C. M., Kipnis, J., Artyomov, M. N., Ulrich, J. D., & Holtzman, D. M.
Affiliations
  • Washington University in St. Louis (US)
  • Federal Almazov North-West Medical Research Centre (RU)
Corresponding author
Holtzman, David M.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2023-03-08
Volume
615
Issue
7953
Pages
668-677
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-023-05788-0
PMC
PMC10258627
OpenAlex
W4323542992
Cited by
609
References
18
Citations by year
2026: 173 · 2025: 170 · 2024: 184 · 2023: 81
FWCI
61.95
Type
journal article
Language
en
Update notices
correction (2024-10-16)
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
  • Zenodo (CERN European Organization for Nuclear Research) (cc-by)
Funders
  • Cure Alzheimer's Fund
  • Children's Discovery Institute (CDI-CORE-2019-813, CDI-CORE-2015-505)
  • Ministry of Science and Higher Education of the Russian Federation (075-15-2022, 075-15-, 075‐15‐2022‐301)
  • Center for Cellular Imaging, Washington University
  • National Institute of Neurological Disorders and Stroke (R01NS090934, RF1NS090934)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
tauopathy, Alzheimer's disease, microglia, T cell infiltration, neurodegeneration, cytotoxic T lymphocytes, T cell exhaustion, interferon-gamma, brain atrophy, innate and adaptive immunity, neuronal loss, primary tauopathies
MeSH terms
Alzheimer Disease, Animals, Brain, Clone Cells, Immunity, Innate, Interferon-gamma, Receptors, Antigen, T-Cell, T-Lymphocytes, T-Lymphocytes, Cytotoxic, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Microglia, Tauopathies, Mice, Plaque, Amyloid, Programmed Cell Death 1 Receptor

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