Bone marrow-derived myeloid cells drive neuroinflammation in Alzheimer's disease: Insights from the FAD4T mouse model

作者：Yidan Pang, Dongjing Jia, Fang Ye, Fei Liu, Jiaqi Li, Siyuan Zhu, Bingqi Wang, Meng Yao, Lin Du, Chunying Yang, Guoji Guo, Cunxiang Ju, Lufeng Yao, Changqing Zhang, Junjie Gao, Qi Hao · 发表于：Journal of Orthopaedic Translation · 年份：2025 · DOI：10.1016/j.jot.2025.06.014 · 被引用次数：4 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Neurogenesis and neuroplasticity mechanisms、Immune cells in cancer

Objective Alzheimer's disease (AD) is marked by amyloid β (Aβ) accumulation, neuroinflammation, and cognitive decline. While neuroinflammation is a key feature of AD, the potential involvement of bone marrow-derived cells in its pathology remains unclear. This study aimed to investigate the role of bone marrow-derived myeloid cells in driving neuroinflammation in AD. Methods We developed a transgenic mouse model (FAD4T) by overexpressing human APPSwe/Ind and PSEN1 M146L/L286V on a C57BL/6J background. FAD 4T mice were characterized for hallmark AD features, including amyloid deposition, glial activation, and cognitive deficits. Additionally, single-cell transcriptomic analysis was performed to profile bone marrow and brain myeloid cells. Bone marrow transplantation experiments were conducted to assess the contribution of bone marrow-derived macrophages to neuroinflammation in AD. Results FAD 4T mice exhibited hallmark AD phenotypes such as amyloid deposition, glial activation, and cognitive impairment, alongside osteoporosis-like changes. Single-cell transcriptomic analysis identified a significant increase in bone marrow-derived macrophages in the brains of FAD 4T mice. These cells showed upregulation of AD-related genes, including Cst7 and Ctsd , suggesting their active role in neuroinflammation. Bone marrow transplantation experiments further confirmed that bone marrow-derived macrophages contributed to the inflammatory processes in the AD brain. Conclusion Our findings de...