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Abstract
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 Aβ in Alzheimer’s disease (AD). While CD11b+CD45low microglia account for the majority of CNS MPs, a small population of CD11b+CD45high CNS MPs is also recognized in AD that surround Aβ plaques. These transcriptionally and pathologically unique CD45high cells have unclear origin and undefined phagocytic characteristics. We have comprehensively validated rapid flow cytometric assays of bulk-phase and amyloid β fibril (fAβ) phagocytosis and applied these to study acutely isolated CNS MPs. Using these methods, we provide novel insights into differential abilities of CD11b+ CD45low and CD45high CNS MPs to phagocytose macroparticles and fAβ under normal, acute, and chronic neuroinflammatory states. CD45high CNS MPs also highly upregulate TREM2, CD11c, and several disease-associated microglia signature genes and have a higher phagocytic capacity for Aβ as compared to CD45low 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+CD45high CNS MPs in neurodegeneration, which if promoted, could be beneficial.
Highlights
Professional phagocytes, such as macrophages and microglia, in the brain internalize particles through pinocytosis, endocytosis, and phagocytosis using a diverse array of receptors
We report the validation of rapid flow cytometric assays of macroparticle and fibrillar Aβ42 phagocytosis, each regulated by distinct phagocytic receptors
We performed an integrative analysis of genes invol ved in phagocytosis or phagoptosis that are expressed by CD11b+CD45high and CD45low CNS MPs using existing population-level RNAseq data from adult WT mice and single-cell RNAseq data from WT and 5xFAD mouse CD45+ CNS MPs [12, 37]. 5,434 genes were identified across both RNAseq datasets with no missing values and among these, we identified 51 phagocytic or phagoptotic genes (Table S3 in Supplementary Material)
Summary
Professional phagocytes, such as macrophages and microglia, in the brain internalize particles through pinocytosis, endocytosis, and phagocytosis using a diverse array of receptors. Phagocytosis typically involves engulfment of particles >0.5 μm in size and is an actin-dependent process unlike pinocytosis and endocytosis, which are clathrin-dependent [1]. Flow-cytometric characterization of CNS phagocytes nervous system (CNS) include microglia, macrophages (collectively called CNS mononuclear phagocytes or CNS MPs), as well as ependymal cells, pericytes, and astrocytes [2,3,4]. In AD, dysregulation of phagocytic mechanisms in chronically activated microglia is associated with progressive amyloid β (Aβ) aggregation and pro-inflammatory neurotoxic responses [9]
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