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Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology.

Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, Tsitsou-Kampeli A, Sarel A, Cahalon L, Schwartz M - Nat Commun (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, 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.

No MeSH data available.


Related in: MedlinePlus

Choroid plexus gateway dysfunction in AD-Tg mice.(a) mRNA expression levels for the genes icam1, vcam1, cxcl10 and ccl2, measured by RT-qPCR, in CPs isolated from 1-, 2-, 4- and 8-month-old AD-Tg mice, shown as fold-change compared with age-matched WT controls (n=6–8 per group; Student's t-test for each time point). (b) Representative microscopic images of CPs of 8-month-old AD-Tg mice and age-matched WT controls, immunostained for the epithelial tight junction molecule Claudin-1 (green), Hoechst nuclear staining (blue) and the integrin ligand, ICAM-1 (red; scale bar, 50 μm). Inserts showing Claudin-1 (green) and ICAM-1 (red) double staining. (c–d) Representative micrographs (c), and quantification (d), of ICAM-1 immunoreactivity in human postmortem CP of young and aged non-CNS-diseased and AD patients (scale bar, 50 μm). (e) Flow cytometry analysis of IFN-γ-expressing immune cells (intracellularly stained, and pre-gated on CD45) in CPs of 8-month-old AD-Tg mice and age-matched WT controls. Shaded histogram represents isotype control (n=4–6 per group; Student's t-test). (f) mRNA expression levels of ifn-γ, measured by RT-qPCR, in CP tissues isolated from 4- and 8-month-old AD-Tg mice, compared with age-matched WT controls (n=5–8 per group; Student's t-test for each time point). In all panels, error bars represent mean±s.e.m.; *P<0.05; **P<0.01; ***P<0.001.
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f1: Choroid plexus gateway dysfunction in AD-Tg mice.(a) mRNA expression levels for the genes icam1, vcam1, cxcl10 and ccl2, measured by RT-qPCR, in CPs isolated from 1-, 2-, 4- and 8-month-old AD-Tg mice, shown as fold-change compared with age-matched WT controls (n=6–8 per group; Student's t-test for each time point). (b) Representative microscopic images of CPs of 8-month-old AD-Tg mice and age-matched WT controls, immunostained for the epithelial tight junction molecule Claudin-1 (green), Hoechst nuclear staining (blue) and the integrin ligand, ICAM-1 (red; scale bar, 50 μm). Inserts showing Claudin-1 (green) and ICAM-1 (red) double staining. (c–d) Representative micrographs (c), and quantification (d), of ICAM-1 immunoreactivity in human postmortem CP of young and aged non-CNS-diseased and AD patients (scale bar, 50 μm). (e) Flow cytometry analysis of IFN-γ-expressing immune cells (intracellularly stained, and pre-gated on CD45) in CPs of 8-month-old AD-Tg mice and age-matched WT controls. Shaded histogram represents isotype control (n=4–6 per group; Student's t-test). (f) mRNA expression levels of ifn-γ, measured by RT-qPCR, in CP tissues isolated from 4- and 8-month-old AD-Tg mice, compared with age-matched WT controls (n=5–8 per group; Student's t-test for each time point). In all panels, error bars represent mean±s.e.m.; *P<0.05; **P<0.01; ***P<0.001.

Mentions: We first examined CP activity in supporting leukocyte trafficking to the CNS along disease progression in the 5XFAD transgenic mouse model of AD (AD-Tg); these mice co-express five mutations associated with familial AD, and develop cerebral Aβ pathology and gliosis as early as 2 months of age24. We found that along the progressive stages of disease pathology, the CP of AD-Tg mice, compared with age-matched wild-type (WT) controls, expressed significantly lower levels of leukocyte homing and trafficking determinants, including intercellular adhesion molecule 1 (icam1), vascular cell adhesion molecule 1 (vcam1), C-X-C motif chemokine 10 (cxcl10) and chemokine C-C motif ligand 2 (ccl2) (Fig. 1a), shown to be upregulated by the CP in response to acute CNS damage and needed for transepithelial migration of leukocytes171819. Immunohistochemical staining for the integrin ligand, ICAM-1, confirmed its reduced expression by the CP epithelium of AD-Tg mice (Fig. 1b). In addition, staining for ICAM-1 in human postmortem brains, showed its age-associated reduction in the CP epithelium, in line with our previous observations25, and quantitative assessment of this effect revealed further decline in AD patients compared with aged individuals without CNS disease (Fig. 1c,d). Since the induction of leukocyte trafficking determinants by the CP is dependent on epithelial IFN-γ signalling17, and IFN-γ levels at the CP were found to be reduced in brain aging2526 and under neurodegenerative conditions20, we next-tested whether the observed effects in AD-Tg mice could reflect loss of IFN-γ availability at the CP. Examining the CP of 5XFAD AD-Tg mice using intracellular staining followed by flow cytometry, revealed significantly lower numbers of IFN-γ-producing cells in this compartment (Fig. 1e), and quantitative real-time PCR (RT-qPCR) analysis confirmed lower mRNA expression levels of ifn-γ at the CP of AD-Tg mice compared with age-matched WT controls (Fig. 1f).


Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology.

Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, Tsitsou-Kampeli A, Sarel A, Cahalon L, Schwartz M - Nat Commun (2015)

Choroid plexus gateway dysfunction in AD-Tg mice.(a) mRNA expression levels for the genes icam1, vcam1, cxcl10 and ccl2, measured by RT-qPCR, in CPs isolated from 1-, 2-, 4- and 8-month-old AD-Tg mice, shown as fold-change compared with age-matched WT controls (n=6–8 per group; Student's t-test for each time point). (b) Representative microscopic images of CPs of 8-month-old AD-Tg mice and age-matched WT controls, immunostained for the epithelial tight junction molecule Claudin-1 (green), Hoechst nuclear staining (blue) and the integrin ligand, ICAM-1 (red; scale bar, 50 μm). Inserts showing Claudin-1 (green) and ICAM-1 (red) double staining. (c–d) Representative micrographs (c), and quantification (d), of ICAM-1 immunoreactivity in human postmortem CP of young and aged non-CNS-diseased and AD patients (scale bar, 50 μm). (e) Flow cytometry analysis of IFN-γ-expressing immune cells (intracellularly stained, and pre-gated on CD45) in CPs of 8-month-old AD-Tg mice and age-matched WT controls. Shaded histogram represents isotype control (n=4–6 per group; Student's t-test). (f) mRNA expression levels of ifn-γ, measured by RT-qPCR, in CP tissues isolated from 4- and 8-month-old AD-Tg mice, compared with age-matched WT controls (n=5–8 per group; Student's t-test for each time point). In all panels, error bars represent mean±s.e.m.; *P<0.05; **P<0.01; ***P<0.001.
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f1: Choroid plexus gateway dysfunction in AD-Tg mice.(a) mRNA expression levels for the genes icam1, vcam1, cxcl10 and ccl2, measured by RT-qPCR, in CPs isolated from 1-, 2-, 4- and 8-month-old AD-Tg mice, shown as fold-change compared with age-matched WT controls (n=6–8 per group; Student's t-test for each time point). (b) Representative microscopic images of CPs of 8-month-old AD-Tg mice and age-matched WT controls, immunostained for the epithelial tight junction molecule Claudin-1 (green), Hoechst nuclear staining (blue) and the integrin ligand, ICAM-1 (red; scale bar, 50 μm). Inserts showing Claudin-1 (green) and ICAM-1 (red) double staining. (c–d) Representative micrographs (c), and quantification (d), of ICAM-1 immunoreactivity in human postmortem CP of young and aged non-CNS-diseased and AD patients (scale bar, 50 μm). (e) Flow cytometry analysis of IFN-γ-expressing immune cells (intracellularly stained, and pre-gated on CD45) in CPs of 8-month-old AD-Tg mice and age-matched WT controls. Shaded histogram represents isotype control (n=4–6 per group; Student's t-test). (f) mRNA expression levels of ifn-γ, measured by RT-qPCR, in CP tissues isolated from 4- and 8-month-old AD-Tg mice, compared with age-matched WT controls (n=5–8 per group; Student's t-test for each time point). In all panels, error bars represent mean±s.e.m.; *P<0.05; **P<0.01; ***P<0.001.
Mentions: We first examined CP activity in supporting leukocyte trafficking to the CNS along disease progression in the 5XFAD transgenic mouse model of AD (AD-Tg); these mice co-express five mutations associated with familial AD, and develop cerebral Aβ pathology and gliosis as early as 2 months of age24. We found that along the progressive stages of disease pathology, the CP of AD-Tg mice, compared with age-matched wild-type (WT) controls, expressed significantly lower levels of leukocyte homing and trafficking determinants, including intercellular adhesion molecule 1 (icam1), vascular cell adhesion molecule 1 (vcam1), C-X-C motif chemokine 10 (cxcl10) and chemokine C-C motif ligand 2 (ccl2) (Fig. 1a), shown to be upregulated by the CP in response to acute CNS damage and needed for transepithelial migration of leukocytes171819. Immunohistochemical staining for the integrin ligand, ICAM-1, confirmed its reduced expression by the CP epithelium of AD-Tg mice (Fig. 1b). In addition, staining for ICAM-1 in human postmortem brains, showed its age-associated reduction in the CP epithelium, in line with our previous observations25, and quantitative assessment of this effect revealed further decline in AD patients compared with aged individuals without CNS disease (Fig. 1c,d). Since the induction of leukocyte trafficking determinants by the CP is dependent on epithelial IFN-γ signalling17, and IFN-γ levels at the CP were found to be reduced in brain aging2526 and under neurodegenerative conditions20, we next-tested whether the observed effects in AD-Tg mice could reflect loss of IFN-γ availability at the CP. Examining the CP of 5XFAD AD-Tg mice using intracellular staining followed by flow cytometry, revealed significantly lower numbers of IFN-γ-producing cells in this compartment (Fig. 1e), and quantitative real-time PCR (RT-qPCR) analysis confirmed lower mRNA expression levels of ifn-γ at the CP of AD-Tg mice compared with age-matched WT controls (Fig. 1f).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, 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.

No MeSH data available.


Related in: MedlinePlus