Bone marrow myelopoiesis dysfunction in Alzheimer’s disease limits monocyte homing to the brain and drives disease progression

: Bone marrow-derived macrophages were shown to play an important role in coping with Alzheimer's disease (AD). Boosting their spontaneous recruitment reduces inflammation and disease pathology and slows cognitive decline in mouse models of amyloidosis. However, the factors limiting their spontaneous homing to the diseased brain remain unclear. In this study, we discovered that monocyte development is impaired in mouse models and in patients. In the 5×FAD mouse model, monocyte differentiation was disrupted due to a maladaptive type I interferon (IFN-I)-mediated bone marrow response. A similar phenotype was found in circulating monocytes from patients with AD. Blocking IFN-I signaling with neutralizing antibodies or reconstituting 5×FAD mice with IFN-I receptor-deficient bone marrow restored myelopoiesis, normalized monocyte phenotypes and ameliorated disease pathology. This was accompanied by increased homing of monocyte-derived macrophages to the brain. Our results reveal a dysfunction in bone marrow myelopoiesis in AD and reinforce the concept that AD progression is driven by maladaptive systemic processes.