The potential of immune checkpoint blockade for fighting against Alzheimer`s disease

The brain has been considered as an autonomous tissue that performs best without any assistance from the immune system. Now, it is now widely accepted, much through our work, that circulating monocytes and CD4+ T cells are needed for supporting brain repair and functional plasticity. We demonstrated that leukocytes can get access to the brain territory through a unique interface, the epithelial layer that forms the blood-CSF-barrier, the choroid plexus epithelium (CP). We discovered by immunogenomic and by immunohistochemistry that in aging and in Alzheimer’s disease (AD) mice this interface is suppressed with respect to its ability to allow leukocyte trafficking. Transiently reducing systemic immunosuppression by blocking the inhibitory immune checkpoint pathways PD-1/PD-L1, regulatory pathways that maintain systemic immune homeostasis, led to recruitment of monocyte-derived macrophages to sites of brain pathology. Using anti-PD-1 antibodies in several mouse models of AD and age-related dementia was found to be effective in reversing cognitive loss, in reducing brain pathology, and in restoring brain homeostasis as determined by the inflammatory molecular profile. Such an approach is not meant to be directed against any disease-escalating factor within the brain, but rather it empowers the immune system of the individual to drive the process of repair. This, approach by directly targeting the immune system, provides addresses numerous factors that go awry in the brain regardless of the primary cause of the disease or disease etiology.