Young bone marrow-derived microglia-like cells improve cognitive function in the aged brain through BDNF-TrkB signalling
Blood-borne macrophages are present in the brain under normal and pathological conditions. Although the complete role of these cells has yet to be determined, emerging evidence shows these cells to be vital during injury and infection, and contribute to the brain's macrophage niche throughout the entirety of an organism's lifespan. This is not always beneficial as macrophages become pro-inflammatory, primed, and hyper-activated with age and disease. One solution is to introduce macrophage precursor cells from young donors into the aged brain to attenuate age- and injury-induced inflammation and cognitive decline. Despite drastic improvements, it remains unclear by which mechanism(s) these cells rejuvenate brain function. To understand this, we generated mice whose CX3CR1-expressing macrophages are selectively depletable using diphtheria toxin. Controlled ablation of donor bone marrow (BM)-derived macrophages from the aged brain was achieved one or three months after transplanting into aged wild type recipients. At three months, the overall brain microglial-niche failed to repopulate from either peripherally- or centrally-derived macrophages after depletion. This was accompanied by severely reduced global monocyte recruitment and a large influx of neutrophils to the brain. Hippocampal-dependent behaviour was unaffected, presumably due to the absence of these cells in the hippocampus during this time point. At one month, BM-derived microglia-like cells were abundant in the hippocampus and their depletion severely impaired improvements in cognitive function and inhibited dendritic spine arborisation in hippocampal neurons. Pharmacological blocking of the brain-derived neurotrophic factor (BDNF) receptor, tropomyosin-related kinase B (TrkB), yielded the same detrimental effects in these mice as depleting the cells. These findings suggest that young BM-derived microglia-like cells could improve cognitive function in aged animals via the BDNF-TrkB signalling pathway during early brain homing and do not require permanent integration for beneficial effects to persist long-term.