Systemic immunity protects the mind: Can immune checkpoint blockade combat Alzheimer’s disease?
It is now widely accepted that immune surveillance is required for supporting brain functional plasticity and repair. Participating cells include the microglia, the resident myeloid immune cells of the brain, circulating monocytes, and CD4+ T cells. Over the years, we demonstrated that leukocytes supporting the brain can gain access to the brain through a unique compartment within the brain territory, the chroid plexus epithelium (CP) at the blood-cerebrospinal fluid-barrier (B-CSF-B), remote from the brain parenchyma. The CP serves as a selective gateway allowing leukocyte entry to the CNS; its activity is controlled by its cytokine milieu, and specifically by IFN-g. We showed that in mouse models of aging and in Alzheimer’s disease (AD), this interface is suppressed in its ability to allow communication between the brain and the circulating leukocytes. We further found that transiently relieving systemic immune suppression could enhance recruitment of disease-modifying leukocytes to sites of brain pathology. Unleashing the immune system could be achieved by blocking inhibitory immune checkpoints, regulatory pathways that normally maintain systemic immune homeostasis and tolerance. Specifically, we found in three mouse models of AD that targeting the inhibitory checkpoints, PD-1/PD-L1 pathway, was effective in reversing cognitive loss, reducing brain inflammation, and mitigating disease pathology. In addition, our emerging understanding of the fate of microglia in AD, based on single cell immunogenomics, has revealed a role of microglia in combating the disease, and suggests that boosting systemic immunity modifies microglial activity. Overall, our results indicate that targeting the immune system rather than brain-specific disease-escalating factors may provide a multi-dimensional therapy for AD.
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