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

Author

Listed:
  • Kuti Baruch

    (Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel)

  • Neta Rosenzweig

    (Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel)

  • Alexander Kertser

    (Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel)

  • Aleksandra Deczkowska

    (Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel)

  • Alaa Mohammad Sharif

    (Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel)

  • Amit Spinrad

    (Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel)

  • Afroditi Tsitsou-Kampeli

    (Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel)

  • Ayelet Sarel

    (Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel)

  • Liora Cahalon

    (Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel)

  • Michal Schwartz

    (Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel)

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.

Suggested Citation

  • Kuti Baruch & Neta Rosenzweig & Alexander Kertser & Aleksandra Deczkowska & Alaa Mohammad Sharif & Amit Spinrad & Afroditi Tsitsou-Kampeli & Ayelet Sarel & Liora Cahalon & Michal Schwartz, 2015. "Breaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8967
    DOI: 10.1038/ncomms8967
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    1. Stefano Suzzi & Tommaso Croese & Adi Ravid & Or Gold & Abbe R. Clark & Sedi Medina & Daniel Kitsberg & Miriam Adam & Katherine A. Vernon & Eva Kohnert & Inbar Shapira & Sergey Malitsky & Maxim Itkin &, 2023. "N-acetylneuraminic acid links immune exhaustion and accelerated memory deficit in diet-induced obese Alzheimer’s disease mouse model," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Mathias Linnerbauer & Tobias Beyer & Lucy Nirschl & Daniel Farrenkopf & Lena Lößlein & Oliver Vandrey & Anne Peter & Thanos Tsaktanis & Hania Kebir & David Laplaud & Rupert Oellinger & Thomas Engleitn, 2023. "PD-L1 positive astrocytes attenuate inflammatory functions of PD-1 positive microglia in models of autoimmune neuroinflammation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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