Abstract # 1715 Transiently breaking immune tolerance by targeting Foxp3+CD4+ regulatory T cells mitigates Alzheimer’s disease pathology

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with unresolved chronic neuroinflammation. Nevertheless, boosting recruitment of immune cells under chronic neurodegenerative conditions in general, and in AD in particular, was shown to attenuate pathology. Our group recently pointed to the brain’s choroid plexus (CP), as a potential selective gateway for the entry of disease-modifying leukocytes to the CNS under injurious conditions. Here, we hypothesized that in AD, suboptimal recruitment of immune cells to the brain is an outcome of systemic immune failure, involving CP gateway dysfunction. Examining the CP of 5XFAD AD transgenic (AD-Tg) mice along disease progression, we found dysfunction of CP gateway activity, which was associated with local CP deficiency in interferon-gamma levels. We show that breaking systemic immune tolerance by transient conditional depletion of Foxp3+ regulatory T cells (Tregs), or pharmacological inhibition of their activity, in AD-Tg mice, augmented IFN-gamma-dependent CP-gateway activity for leukocyte trafficking. The activation of this immune-brain axis was followed by accumulation of immunoregulatory cells at cerebral sites of amyloid-beta pathology, plaque clearance, and mitigation of cognitive decline. Conversely, augmenting systemic Treg levels in AD-Tg mice was associated with accelerated disease pathology. Collectively, our findings identify Treg-mediated immune suppression in AD as an obstacle to mounting a systemic immune response for the resolution of neuroinflammation, and suggest a novel therapeutic approach for treating AD.