ABSTRACT
Microglia, the primary immune cells in the brain, sense pathogens and tissue damage, stimulate cytokine production, and phagocytosis to maintain homeostasis. Accumulation of amyloid-ß peptides (Aß) in the brain triggers the onset of Alzheimer's disease (AD). Accordingly, promotion of Aß clearance represents a promising strategy for AD therapy. We previously demonstrated that primary-cultured rat microglia phagocytose Aß, and that transplantation of these cells ameliorates the Aß burden in brains of Aß-injected rats. In this study, we demonstrate that stimulation with colony-stimulating factor-1 efficiently differentiates mouse bone marrow cells into bone marrow-derived microglia-like (BMDML) cells that express markers for microglia, including the recently identified transmembrane protein 119. BMDML cells effectively phagocytose Aß in vitro, with effects comparable to primary-cultured mouse microglia and greater than peritoneal macrophages. RT-qPCR analysis for cytokine mRNA levels revealed that BMDML cells polarize to a relatively anti-inflammatory state under non-stimulated and inflammatory conditions but exert a pro-inflammatory reaction after lipopolysaccharide treatment. Moreover, BMDML cells hippocampally injected into a mouse model of AD are morphologically similar to the ramified and amoeboid types of residential microglia. Comparisons with simulations assuming a uniform distribution of cells suggest that BMDML cells migrate directionally toward Aß plaques. We also detected Aß phagocytosis by BMDML cells, concomitant with a reduction in the number and area of Aß plaques. Finally, we observed amelioration of cognitive impairment in a mouse model of AD after hippocampal injection of BMDML cells. Our results suggest that BMDML cells have potential as a cell-based disease-modifying therapy against AD.
