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

Abstract

Background: Accumulation of amyloid β (Aβ) is one of the main hallmarks of Alzheimer’s disease (AD). The enhancement of Aβ clearance may provide therapeutic means to restrict AD pathology. The cellular responses to different forms of Aβ in monocytic cells are poorly known. We aimed to study whether different forms of Aβ induce inflammatory responses in monocytic phagocytes and how Aβ may affect monocytic cell survival and function to retain phagocytosis in Aβ-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 Aβ42 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 Aβ 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 Aβ plaques was determined after intrahippocampal transplantation in vivo.Results: Freshly solubilized Aβ induced calcium oscillations, which persisted after removal of the stimulus. After few hours of aggregation, Aβ was not able to induce oscillations in monocytic cells. Instead, lipopolysaccharide (LPS) induced calcium responses divergent from Aβ-induced response. Furthermore, while LPS induced massive production of pro-inflammatory cytokines, neither synthetic Aβ species nor native Aβ 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 Aβ and exhibited phagocytic activity towards native fibrillar Aβ deposits and congophilic Aβ plaques.Conclusion: Monocytic cells carry diverse cellular responses to Aβ and inflammatory stimulus LPS. Even though Aβ 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 Aβ-laden brain.

Granulocyte-macrophage colony-stimulating factor neuroprotective activities in Alzheimer’s disease mice

“…One way that GM-CSF facilitates improvements in brain function is by recruiting monocyte-macrophages from the peripheral blood into the brain and affects clearance of Aβ plaques (Butovsky et al, 2007, Darlington et al, 2015, El Khoury et al, 2007, Fu et al, 2016, Hohsfield and Humpel, 2015, Malm et al, 2005, Savchenko et al, 2016, Simard et al, 2006, Zuroff et al, 2017). Additionally, increases in neural cell connections in brains of GM-CSF-treated subjects may provide insights into the association between memory improvements and control of innate and adaptive immune responses.…”

Expression Profiling of Cytokine, Cholinergic Markers, and Amyloid-β Deposition in the APPSWE/PS1dE9 Mouse Model of Alzheimer’s Disease Pathology

“…In AD, brain amyloid plaques and tangles are related to local stimulation of innate immune and inflammatory responses, and astrocytes, microglia, and neurons are responsible for the inflammatory reaction [ 4 ]. A similar intercellular and intracellular signaling process induced by cytokines occurres in microglia, astrocytes, and peripheral cells[ 5–7 ].…”

Microglial amyloid beta clearance is driven by PIEZO1 channels

“…Ca 2+ signaling is critical for microglial protective functions, and it is dysfunctional in AD (67)(68)(69). However, the exact mechanisms or time course of these dysfunctions have not been extensively studied.…”