Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology.
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.
Department of Neurobiology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
Kuti
K
Baruch
Department of Neurobiology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
Neta
N
Rosenzweig
Department of Neurobiology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
Alexander
A
Kertser
Department of Neurobiology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
Aleksandra
A
Deczkowska
Department of Neurobiology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
Alaa Mohammad
AM
Sharif
Department of Neurobiology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
Amit
A
Spinrad
Department of Neurobiology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
Afroditi
A
Tsitsou-Kampeli
Department of Neurobiology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
Ayelet
A
Sarel
Department of Neurobiology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
Liora
L
Cahalon
Department of Neurobiology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
Michal
M
Schwartz
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018891:Dentate Gyrus / Q000473:pathology / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D000068717:Glatiramer Acetate / Q000494:pharmacology; D007108:Immune Tolerance; D056747:Immunomodulation; D051379:Mice; D008822:Mice, Transgenic; D012313:RNA / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000068717:Glatiramer Acetate; D012313:RNA