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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

Interference with Foxp3+ Treg cell activity using p300 inhibitor mitigates AD pathology.(a,b) Aged WT mice (18 months) were used to test the effect of p300i on IFN-γ-expressing cell levels in the CP and spleen. Mice were treated with either p300i or vehicle (DMSO) for a period of 1 week, and examined a day after cessation of treatment. Representative flow cytometry plots showing elevation in the frequencies of CD4+ T cells expressing IFN-γ in the spleen (a), and IFN-γ-expressing immune cell numbers in the CP (b), following p300i treatment. (c–e) Representative microscopic images (c), and quantitative analysis, of Aβ plaque burden in the brains of 10-month-old AD-Tg mice that received either p300i or vehicle (DMSO) for a period of 1 week, and were subsequently examined after 3 additional weeks. Brains were immunostained for Aβ plaques (red) and by Hoechst nuclear staining (n=5 per group; Scale bar, 250 μm). Mean Aβ plaque area and plaque numbers were quantified in the hippocampal DG (d) and the fifth layer of the cerebral cortex (e), in 6 μm brain slices (n=5–6 per group; Student's t-test). (f–h) Schematic representation (f) of the p300i treatment (or DMSO, vehicle) regimen to the different groups of AD-Tg mice at the age of 7 months, in either one or two treatment courses. Change in mean of Aβ plaque percentage coverage of the cerebral cortex (fifth layer) (g), and the change in mean cerebral soluble Aβ1-40 and Aβ1-42 protein levels (h), relative to the untreated AD-Tg group (Aβ1-40 and Aβ1-42 mean level in untreated group, 90.5±11.2 and 63.8±6.8 pg/mg total portion, respectively; n=5–6 per group; one-way ANOVA followed by Newman–Keuls post hoc analysis). In all panels, error bars represent mean±s.e.m.; *P<0.05; **P<0.01.
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f5: Interference with Foxp3+ Treg cell activity using p300 inhibitor mitigates AD pathology.(a,b) Aged WT mice (18 months) were used to test the effect of p300i on IFN-γ-expressing cell levels in the CP and spleen. Mice were treated with either p300i or vehicle (DMSO) for a period of 1 week, and examined a day after cessation of treatment. Representative flow cytometry plots showing elevation in the frequencies of CD4+ T cells expressing IFN-γ in the spleen (a), and IFN-γ-expressing immune cell numbers in the CP (b), following p300i treatment. (c–e) Representative microscopic images (c), and quantitative analysis, of Aβ plaque burden in the brains of 10-month-old AD-Tg mice that received either p300i or vehicle (DMSO) for a period of 1 week, and were subsequently examined after 3 additional weeks. Brains were immunostained for Aβ plaques (red) and by Hoechst nuclear staining (n=5 per group; Scale bar, 250 μm). Mean Aβ plaque area and plaque numbers were quantified in the hippocampal DG (d) and the fifth layer of the cerebral cortex (e), in 6 μm brain slices (n=5–6 per group; Student's t-test). (f–h) Schematic representation (f) of the p300i treatment (or DMSO, vehicle) regimen to the different groups of AD-Tg mice at the age of 7 months, in either one or two treatment courses. Change in mean of Aβ plaque percentage coverage of the cerebral cortex (fifth layer) (g), and the change in mean cerebral soluble Aβ1-40 and Aβ1-42 protein levels (h), relative to the untreated AD-Tg group (Aβ1-40 and Aβ1-42 mean level in untreated group, 90.5±11.2 and 63.8±6.8 pg/mg total portion, respectively; n=5–6 per group; one-way ANOVA followed by Newman–Keuls post hoc analysis). In all panels, error bars represent mean±s.e.m.; *P<0.05; **P<0.01.

Mentions: The findings above, which suggested that Treg-mediated systemic immune suppression interferes with the ability to fight AD pathology, are reminiscent of the function attributed to Tregs in cancer immunology, in which these cells hinder the ability of the immune system to mount an effective anti-tumour response383940. We therefore tested p300i (C646), a nonpeptidic inhibitor of the histone acetyltransferase p300 (ref. 41); although histone acetyltransferases can have a direct effect on the brain42, p300i was found to regulate T-cell function by impairing Treg suppressive activities without affecting effector T-cell protective responses43. We found that mice treated with p300i, compared with vehicle (dimethylsulphoxide (DMSO))-treated controls, showed elevated levels of systemic IFN-γ-expressing cells in the spleen (Fig. 5a), as well as in the CP (Fig. 5b). We next treated AD-Tg mice at the age of 10 months (a stage of robust cerebral plaque pathology) with p300i over a course of 1 week, and examined the mice 3 weeks later for cerebral Aβ plaque burden. Immunohistochemical analysis revealed a significant reduction in cerebral Aβ plaque load in the p300i-treated AD-Tg mice relative to vehicle-treated controls (Fig. 5c–e). We also tested whether the effect on plaque pathology following a single course of treatment would last beyond 3 weeks, and if so, whether additional courses of treatment would be effective over a longer period of time. We compared AD-Tg mice that received a single course of p300i treatment and were examined 2 months later, to an age-matched group that received two treatment courses during this period, with a 1-month interval in between (schematically depicted in Fig. 5f). We found that the reduction of cerebral plaque load was evident even 2 months after a single course of treatment, but was stronger in mice that received two courses of treatment at a 1-month interval (Fig. 5g).


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)

Interference with Foxp3+ Treg cell activity using p300 inhibitor mitigates AD pathology.(a,b) Aged WT mice (18 months) were used to test the effect of p300i on IFN-γ-expressing cell levels in the CP and spleen. Mice were treated with either p300i or vehicle (DMSO) for a period of 1 week, and examined a day after cessation of treatment. Representative flow cytometry plots showing elevation in the frequencies of CD4+ T cells expressing IFN-γ in the spleen (a), and IFN-γ-expressing immune cell numbers in the CP (b), following p300i treatment. (c–e) Representative microscopic images (c), and quantitative analysis, of Aβ plaque burden in the brains of 10-month-old AD-Tg mice that received either p300i or vehicle (DMSO) for a period of 1 week, and were subsequently examined after 3 additional weeks. Brains were immunostained for Aβ plaques (red) and by Hoechst nuclear staining (n=5 per group; Scale bar, 250 μm). Mean Aβ plaque area and plaque numbers were quantified in the hippocampal DG (d) and the fifth layer of the cerebral cortex (e), in 6 μm brain slices (n=5–6 per group; Student's t-test). (f–h) Schematic representation (f) of the p300i treatment (or DMSO, vehicle) regimen to the different groups of AD-Tg mice at the age of 7 months, in either one or two treatment courses. Change in mean of Aβ plaque percentage coverage of the cerebral cortex (fifth layer) (g), and the change in mean cerebral soluble Aβ1-40 and Aβ1-42 protein levels (h), relative to the untreated AD-Tg group (Aβ1-40 and Aβ1-42 mean level in untreated group, 90.5±11.2 and 63.8±6.8 pg/mg total portion, respectively; n=5–6 per group; one-way ANOVA followed by Newman–Keuls post hoc analysis). In all panels, error bars represent mean±s.e.m.; *P<0.05; **P<0.01.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4557123&req=5

f5: Interference with Foxp3+ Treg cell activity using p300 inhibitor mitigates AD pathology.(a,b) Aged WT mice (18 months) were used to test the effect of p300i on IFN-γ-expressing cell levels in the CP and spleen. Mice were treated with either p300i or vehicle (DMSO) for a period of 1 week, and examined a day after cessation of treatment. Representative flow cytometry plots showing elevation in the frequencies of CD4+ T cells expressing IFN-γ in the spleen (a), and IFN-γ-expressing immune cell numbers in the CP (b), following p300i treatment. (c–e) Representative microscopic images (c), and quantitative analysis, of Aβ plaque burden in the brains of 10-month-old AD-Tg mice that received either p300i or vehicle (DMSO) for a period of 1 week, and were subsequently examined after 3 additional weeks. Brains were immunostained for Aβ plaques (red) and by Hoechst nuclear staining (n=5 per group; Scale bar, 250 μm). Mean Aβ plaque area and plaque numbers were quantified in the hippocampal DG (d) and the fifth layer of the cerebral cortex (e), in 6 μm brain slices (n=5–6 per group; Student's t-test). (f–h) Schematic representation (f) of the p300i treatment (or DMSO, vehicle) regimen to the different groups of AD-Tg mice at the age of 7 months, in either one or two treatment courses. Change in mean of Aβ plaque percentage coverage of the cerebral cortex (fifth layer) (g), and the change in mean cerebral soluble Aβ1-40 and Aβ1-42 protein levels (h), relative to the untreated AD-Tg group (Aβ1-40 and Aβ1-42 mean level in untreated group, 90.5±11.2 and 63.8±6.8 pg/mg total portion, respectively; n=5–6 per group; one-way ANOVA followed by Newman–Keuls post hoc analysis). In all panels, error bars represent mean±s.e.m.; *P<0.05; **P<0.01.
Mentions: The findings above, which suggested that Treg-mediated systemic immune suppression interferes with the ability to fight AD pathology, are reminiscent of the function attributed to Tregs in cancer immunology, in which these cells hinder the ability of the immune system to mount an effective anti-tumour response383940. We therefore tested p300i (C646), a nonpeptidic inhibitor of the histone acetyltransferase p300 (ref. 41); although histone acetyltransferases can have a direct effect on the brain42, p300i was found to regulate T-cell function by impairing Treg suppressive activities without affecting effector T-cell protective responses43. We found that mice treated with p300i, compared with vehicle (dimethylsulphoxide (DMSO))-treated controls, showed elevated levels of systemic IFN-γ-expressing cells in the spleen (Fig. 5a), as well as in the CP (Fig. 5b). We next treated AD-Tg mice at the age of 10 months (a stage of robust cerebral plaque pathology) with p300i over a course of 1 week, and examined the mice 3 weeks later for cerebral Aβ plaque burden. Immunohistochemical analysis revealed a significant reduction in cerebral Aβ plaque load in the p300i-treated AD-Tg mice relative to vehicle-treated controls (Fig. 5c–e). We also tested whether the effect on plaque pathology following a single course of treatment would last beyond 3 weeks, and if so, whether additional courses of treatment would be effective over a longer period of time. We compared AD-Tg mice that received a single course of p300i treatment and were examined 2 months later, to an age-matched group that received two treatment courses during this period, with a 1-month interval in between (schematically depicted in Fig. 5f). We found that the reduction of cerebral plaque load was evident even 2 months after a single course of treatment, but was stronger in mice that received two courses of treatment at a 1-month interval (Fig. 5g).

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