Title : Bone marrow-derived microglia may have a clinical value for treatment of Alzheimer’s disease
Abstract:
The CXCRS/CXL12 axis is a major signal transduction involved in inflammation, cell migration, haematopoiesis and cell homing in the bone marrow. Inhibition of this axis with AMD3100, a reversible antagonist of CXCR4, attenuates the neuroinflammation and mobilizes endogenous hematopoietic stem cells (HSCs) from the bone marrow into the periphery. These cells can self-renew, proliferate, cross the blood-brain barrier, promote brain repair by inducing neurogenesis, releasing anti-inflammatory cytokines and hematopoietic growth factors. and interacting with resident neuroglia and transdifferentiating into microglia-like cells. We chronically treated the 3xTg mice model of Alzheimer's disease (AD) with 5mg AMD3100 for four months. The treatment significantly improved memory deficits and attenuate AD pathology. Another finding from our lab showed that AMD3100 treatment upregulates monocarboxylate transport 1 (MCT1), the major L-lactate transporter in the brain. The combined treatment of AMD3100 and exogenous lactate resulted in a significant beneficial effect compared to the untreated groups and each component alone regarding cognitive/memory functions as well as alleviated pathology with no adverse effects. To conclude, the inhibition of the CXCL12/CXCR4 axis result in prevention of neuroinflammation via mobilization of HSCs to the bloodstream, suggesting that microglia-targeted therapy may be an effective strategy for the treatment of Alzheimer's disease.
