Fighting Alzheimer's Disease by Unleashing the Innate and Adaptive Immune Cells Michal Schwartz Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel The brain is no longer considered a completely autonomous tissue with respect to its immune activity. Rather, immune surveillance is required for supporting brain functional plasticity and repair. Essential immune cells include the microglia, the resident myeloid immune cells of the brain, circulating monocytes, and CD4+ T cells. Both microglial activity and surveillance by systemic immune cells are under tight control, to allow risk-free benefit from such immunological mechanisms. We found that access of circulating leukocytes to the brain is controlled by the choroid plexus epithelium (CP) at the blood-cerebrospinal fluid-barrier (B-CSF-B). Using immunological and immunogenomic tools, we discovered that in brain aging and under neurodegenerative conditions, this interface does not optimally function to allow brain repair. We further showed in mouse models of Alzheimer's disease (AD), that activating the immune system by transiently blocking the inhibitory PD-1/PD-L1 immune checkpoint pathway, needed to maintain memory T cells under control, drives an immune-dependent cascade of processes that start in the periphery and culminate within the brain. This intervention is effective in modifying the diseased brain milieu, reversing cognitive loss, reducing brain inflammation, and mitigating disease pathology. In addition, our studies revealed that microglial activity is also tightly regulated, protecting the fragile brain from excessive immune activity; accordingly, microglial activation under pathological conditions requires reducing their inhibitory 'microglial checkpoints'. Overall, our results indicate that targeting systemic and local immune cells rather than brain-specific disease-escalating factors may provide a multi-dimensional disease-modifying therapy for AD.
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