Bone-Marrow-Derived Microglia-Like Cells Ameliorate Brain Amyloid Pathology and Cognitive Impairment in a Mouse Model of Alzheimer’s Disease

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-β peptides (Aβ) in the brain triggers the onset of Alzheimer's disease (AD). Accordingly, promotion of Aβ clearance represents a promising strategy for AD therapy. We previously demonstrated that primary-cultured rat microglia phagocytose Aβ, and that transplantation of these cells ameliorates the Aβ burden in brains of Aβ-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 Aβ 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 Aβ plaques. We also detected Aβ phagocytosis by BMDML cells, concomitant with a reduction in the number and area of Aβ 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.

Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer’s disease

“…The cytokine stimulates the clearance of Aβ 42 by microglia and in ltrating bone marrow-derived cells (17). In line with these ndings, hippocampal injection of mCSF in AD mouse model induced the differentiation of bone marrow cells into bone marrow-derived microglia (BMDM), which resulted in improved cognitive decline (18). IL-34, triggering receptor expressed on myeloid cells 2 (TREM2) and its adaptor DNAX-activating protein of 12 KDa (DAP12) have also an important role in the pathology.…”

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

“…As monocyte‐derived repopulating cells would have a potentially different response to systemic stimuli compared to normal repopulating microglia, this is also an issue to contemplate. In contrast, it has been shown that bone marrow‐derived cells are much more efficient in clearing amyloid beta deposits compared to their endogenous counterparts (Kawanishi et al, ; Simard, Soulet, Gowing, Julien, & Rivest, ) and so monocyte repopulation would potentially be more efficient in AD.…”

Crosstalk of Brain and Bone—Clinical Observations and Their Molecular Bases

“…In addition to the molecular mediators secreted by bone, bone marrow-derived cells were identified to enter the systemic circulation and migrate into the injured brain [ 8 ]. In preclinical studies, bone marrow-derived microglia-like cells were shown to modulate amyloid pathology by restricting Aβ plaque formation and by supporting Aβ plaque clearance, which improved cognitive impairment [ 366 , 367 , 368 ]. Therefore, recent attempts employed hematopoietic stem cells mobilized from bone marrow into the peripheral blood for autologous microglia-like cell preparation [ 369 ], using specific antibodies to convert bone marrow cells into trafficking microglia-like cells [ 367 ].…”