Bone marrow B lymphopoiesis accelerates early cerebral amyloid pathology

Bone marrow is a major source of hematogenous cells that orchestrate brain immunity. However, alterations in the bone marrow hematopoietic system in patients with Alzheimer's disease (AD) and their potential impacts on neuroinflammation and cerebral β-amyloid (Aβ) pathology remain unknown. Here, we report that Aβ accumulates within the bone marrow of patients with AD and is particularly concentrated in the central nervous system-surrounding bones. In 5 × FAD and APP/PS1 mice, two classic mouse AD models, Aβ accumulates within the skull bone marrow prior to substantial cerebral Aβ deposits. Flow cytometry and cell tracking analyses demonstrated that these AD mice exhibit enhanced bone marrow hematopoiesis in B lymphoid lineages, specifically an increase in age-associated B cells (ABCs), accompanied by heightened output of these cells into the brain parenchyma. Furthermore, intracranial Aβ injection into IL-6 knockout mice revealed that Aβ promotes B lymphocyte generation, particularly ABCs, via IL-6 signaling. Single-cell sequencing analysis following intracerebroventricular ABCs injection, combined with in vitro microglial culture studies, demonstrated that bone marrow-derived ABCs directly augment microglial reactivity, ultimately exacerbating Aβ neuropathology and cognitive deficits in AD models. Notably, blockade of IL-6R restricts B-cell activity and ABCs in the bone marrow, delays cerebral Aβ pathology and improves cognition. Our findings reveal the potential involvement of bone marrow-derived B cells in the early cerebral amyloid pathology in two mouse AD models and suggest that these B cells may serve as potential therapeutic candidates for patients with AD.