Brain–immune communication points during aging and neurodegenerative disease. In a young individual, the peripheral immune system promotes CNS immune surveillance via the CP. Immune activities are controlled by anti-inflammatory cytokines, T regulatory cell function, and checkpoint receptors and ligands (such as PD-1/PD-L1) expressed on T cells, antigen-presenting cells, and possibly on the CP epithelium itself. With aging, dysregulation of peripheral immunity (thymic involution, increase in the systemic levels of myeloid-derived suppressor cells (MDSCs), and exhausted T cells), and CP-specific mechanisms (IFN-I, decrease in local IFN-γ levels) hamper supportive brain–immune cross-talk and promote accumulation of damage in the brain (neurodegeneration).