Journal Article Ahead of print
PubMed: 42711429 DOI: 10.1038/s41593-026-02417-7
Bone marrow myelopoiesis dysfunction in Alzheimer's disease limits monocyte homing to the brain and drives disease progression.
Nat Neurosci
Authors: Miguel Angel Abellanas, Leyre Basurco, Maitreyee Purnapatre, Chiara Burgaletto, Giulia Castellani, Sarah Phoebeluc Colaiuta, Javier Maria Peralta-Ramos, Angham Ibraheem, Sama Murad, Paola Antonello, Mariangeles Kovacs, Yuliya Androsova, Bar Nathansohn, Hannah Partney, Liora Cahalon, Rafael Valdes-Mas, Joseph M Josephides, Tomer M Salame, Maria Espelosin, Mar Cuadrado-Tejedor, Ana Garcia-Osta, Aleksandra Deczkowska, Michal Schwartz
Affiliations
- Brain Sciences Department, Weizmann Institute of Science, Rehovot, Israel.
- Brain Sciences Department, Weizmann Institute of Science, Rehovot, Israel.
- Unit of Neuropharmacology and Translational Neurosciences, Oasi Research Institute-IRCCS, Troina, Italy.
- Brain-Immune Communication Lab, Institut Pasteur, Université Paris Cité, INSERM U1224, Paris, France.
- Center for Applied Medical Research (CIMA), Universidad de Navarra, Pamplona, Spain.
- Institut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics Hub, Paris, France.
- Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel.
- Brain-Immune Communication Lab, Institut Pasteur, Université Paris Cité, INSERM U1224, Paris, France.
- Brain Sciences Department, Weizmann Institute of Science, Rehovot, Israel.
Abstract
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.
MeSH
Monocytes, Bone Marrow, Alzheimer Disease, Macrophages, Brain, Disease Progression, Pathology, Phenotype, Myelopoiesis