Aβ and Inflammatory Stimulus Activate Diverse Signaling Pathways in Monocytic Cells: Implications in Retaining Phagocytosis in Aβ-Laden Environment

Background: Accumulation of amyloid beta (A beta) is one of the main hallmarks of Alzheimer's disease (AD). The enhancement of A beta clearance may provide therapeutic means to restrict AD pathology. The cellular responses to different forms of A beta in monocytic cells are poorly known. We aimed to study whether different forms of A beta induce inflammatory responses in monocytic phagocytes and how A beta may affect monocytic cell survival and function to retain phagocytosis in A beta-laden environment. Methods: Monocytic cells were differentiated from bone marrow hematopoietic stem cells (HSC) in the presence of macrophage-colony stimulating factor. Monocytic cells were stimulated with synthetic A beta 42 and intracellular calcium responses were recorded with calcium imaging. The formation of reactive oxygen species (ROS), secretion of cytokines and cell viability were also assessed. Finally, monocytic cells were introduced to native A beta deposits ex vivo and the cellular responses in terms of cell viability, pro-inflammatory activation and phagocytosis were determined. The ability of monocytic cells to phagocytose A beta plaques was determined after intrahippocampal transplantation in vivo. Results: Freshly solubilized A beta induced calcium oscillations, which persisted after removal of the stimulus. After few hours of aggregation, A beta was not able to induce oscillations in monocytic cells. Instead, lipopolysaccharide (LPS) induced calcium responses divergent from A beta-induced response. Furthermore, while LPS induced massive production of pro-inflammatory cytokines, neither synthetic A beta species nor native A beta deposits were able to induce pro-inflammatory activation of monocytic cells, contrary to primary microglia. Finally, monocytic cells retained their viability in the presence of A beta and exhibited phagocytic activity towards native fibrillar A beta deposits and congophilic A beta plaques. Conclusion: Monocytic cells carry diverse cellular responses to A beta and inflammatory stimulus LPS. Even though, A beta species cause specific responses in calcium signaling, they completely lack the ability to induce pro-inflammatory phenotype of monocytic cells. Monocytes retain their viability and function in A beta-laden brain.