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Cited by 491Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsT-cell and B-cell Immunology

Breaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology

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Baruch, Kuti, Rosenzweig, Neta, Kertser, Alexander, Deczkowska, Aleksandra, Sharif, Alaa Mohammad, Spinrad, Amit, Tsitsou-Kampeli, Afroditi, Sarel, Ayelet +2 more·2015·Nature Communications
DOI 10.1038/ncomms8967PMC PMC4557123
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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder in which chronic neuroinflammation contributes to disease escalation. Nevertheless, while immunosuppressive drugs have repeatedly failed in treating this disease, recruitment of myeloid cells to the CNS was shown to play a reparative role in animal models. Here we show, using the 5XFAD AD mouse model, that transient depletion of Foxp3 + regulatory T cells (Tregs), or pharmacological inhibition of their activity, is followed by amyloid-β plaque clearance, mitigation of the neuroinflammatory response and reversal of cognitive decline. We further show that transient Treg depletion affects the brain’s choroid plexus, a selective gateway for immune cell trafficking to the CNS, and is associated with subsequent recruitment of immunoregulatory cells, including monocyte-derived macrophages and Tregs, to cerebral sites of plaque pathology. Our findings suggest targeting Treg-mediated systemic immunosuppression for treating AD.

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  • Depletion of Treg cells restores the secretion of IFN-γ and the function of the choroid plexus.

    “Depletion of Treg cells restored the secretion of IFN-γ and the function of CP.150”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [150]

    The Results section (page unavailable) reports that transient Treg depletion increased choroid-plexus markers of leukocyte trafficking in AD-model mice, suggesting improved CP gateway activity. It proposes increased IFN-γ availability as the mechanism, while the Discussion reports more systemic IFN-γ-producing cells; neither passage establishes that IFN-γ secretion itself was restored. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • In a 5xFAD AD mouse model, secretion of IFN-γ from the choroid plexus may be suppressed by Treg cells.

    “Using a 5xFAD AD mouse model, found that the secretion of IFN-γ from CP may be suppressed by Treg cells.”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [150]

    The Results sections on CP gateway dysfunction and Treg depletion report fewer IFN-γ-producing cells and lower IFN-γ expression at the CP in 5XFAD mice, and suggest that Treg depletion increases IFN-γ availability there. They do not establish that the CP secretes IFN-γ or that Tregs suppress its secretion from the CP; the reported Treg-mediated effect is systemic rather than direct. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Reduced IFN-γ at the choroid plexus is also found in neurodegenerative diseases, including ALS and AD.

    “This phenomenon was also found in neurodegenerative diseases, including ALS and AD.149,150”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [150]

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Authors
Baruch, K., Rosenzweig, N., Kertser, A., Deczkowska, A., Sharif, A. M., Spinrad, A., Tsitsou-Kampeli, A., Sarel, A., Cahalon, L., & Schwartz, M.
Affiliations
Weizmann Institute of Science (IL)
Corresponding author
  • Baruch, Kuti
  • Schwartz, Michal
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2015-08-18
Volume
6
Issue
1
Pages
7967-7967
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms8967
PMC
PMC4557123
OpenAlex
W2200279205
Cited by
491
References
12
Citations by year
2026: 30 · 2025: 38 · 2024: 52 · 2023: 63 · 2022: 59 · 2021: 64 · 2020: 43 · 2019: 43 · 2018: 32 · 2017: 32 · 2016: 31 · 2015: 4
FWCI
17.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • University of Oxford
  • European Commission (279017)
  • Hebrew University of Jerusalem
  • Medical Research Council (MR/L022656/1)
  • FP7 Ideas: European Research Council (232835)
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 › T-cell and B-cell Immunology
Keywords
Alzheimer's disease, Foxp3+ regulatory T cells, Treg depletion, immune tolerance, neuroinflammation, amyloid plaques, 5xFAD mice, choroid plexus, myeloid cell recruitment, monocyte-derived macrophages, cognitive decline, immunosuppression, neurodegeneration
MeSH terms
Glatiramer Acetate, Alzheimer Disease, Animals, Gene Expression Regulation, Immune Tolerance, Mice, Transgenic, RNA, Amyloid beta-Protein Precursor, Dentate Gyrus, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Immunomodulation

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