Bone marrow B lymphopoiesis accelerates early cerebral amyloid pathology by Jing Zhang & Wenting Fang & Hanchen Liu & Ran Li & Zhibao Zhu & Xin Wu & Shaobo Yao & Ying Fu & Rui Li & Wanjin Chen & Qinyong Ye & Qiang Liu & Xiaochun Chen instant download

Bone marrow B lymphopoiesis accelerates early cerebral amyloid pathology by Jing Zhang & Wenting Fang & Hanchen Liu & Ran Li & Zhibao Zhu & Xin Wu & Shaobo Yao & Ying Fu & Rui Li & Wanjin Chen & Qinyong Ye & Qiang Liu & Xiaochun Chen instant download

Bone marrow is a major source of hematogenous cells that orchestrate brain immunity. However, alterations in the bone marrowhematopoietic system in patients with Alzheimer’s disease (AD) and their potential impacts on neuroinflammation and cerebralβ-amyloid (Aβ) pathology remain unknown. Here, we report that Aβ accumulates within the bone marrow of patients with AD andis particularly concentrated in the central nervous system-surrounding bones. In 5 × FAD and APP/PS1 mice, two classic mouse ADmodels, Aβ accumulates within the skull bone marrow prior to substantial cerebral Aβ deposits. Flow cytometry and cell trackinganalyses demonstrated that these AD mice exhibit enhanced bone marrow hematopoiesis in B lymphoid lineages, specifically anincrease 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, particularlyABCs, via IL-6 signaling. Single-cell sequencing analysis following intracerebroventricular ABCs injection, combined with in vitro1234567890();,:microglial culture studies, demonstrated that bone marrow-derived ABCs directly augment microglial reactivity, ultimatelyexacerbating Aβ neuropathology and cognitive deficits in AD models. Notably, blockade of IL-6R restricts B-cell activity and ABCs inthe bone marrow, delays cerebral Aβ pathology and improves cognition. Our findings reveal the potential involvement of bonemarrow-derived B cells in the early cerebral amyloid pathology in two mouse AD models and suggest that these B cells may serveas potential therapeutic candidates for patients with AD.Signal Transduction and Targeted Therapy (2025) 10:312 ;