Differential Phagocytic Properties of CD45low Microglia and CD45high Brain Mononuclear Phagocytes-Activation and Age-Related Effects

In the central nervous system (CNS), microglia are innate immune mononuclear phagocytes (CNS MPs) that can phagocytose infectious particles, apoptotic cells, neurons, and pathological protein aggregates, such as A beta in Alzheimer's disease (AD). While CD11b(+)CD45(low) microglia account for the majority of CNS MPs, a small population of CD11b(+)CD45(high) CNS MPs is also recognized in AD that surround A beta plaques. These transcriptionally and pathologically unique CD45(high) cells have unclear origin and undefined phagocytic characteristics. We have comprehensively validated rapid flow cytometric assays of bulk-phase and amyloid beta fibril (fA beta) phagocytosis and applied these to study acutely isolated CNS MPs. Using these methods, we provide novel insights into differential abilities of CD11b(+)CD45(low) and CD45(high) CNS MPs to phagocytose macroparticles and fA beta under normal, acute, and chronic neuroinflammatory states. CD45(high) CNS MPs also highly upregulate TREM2, CD11c, and several disease-associated microglia signature genes and have a higher phagocytic capacity for A beta as compared to CD45(low) microglia in the 5xFAD mouse model of AD that becomes more apparent with aging. Our data suggest an overall pro-phagocytic and protective role for CD11b(+)CD45(high) CNS MPs in neurodegeneration, which if promoted, could be beneficial.