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

Journal of orthopaedic translation 2025

Pang Y, Jia D, Ye F, Liu F, Li J, Zhu S, Wang B, Yao M, Du L, Yang C, Guo G, Ju C, Yao L, Zhang C, Gao J, Qi H

Abstract

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. FAD4T 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: FAD4T 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 FAD4T 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 demonstrate that bone marrow-derived myeloid cells infiltrate the brain and might play a critical role in driving neuroinflammation in AD. Targeting these cells may represent a novel therapeutic strategy for mitigating inflammation and disease progression in AD. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Our findings suggest that bone marrow-derived inflammation play a critical role in AD-associated inflammation, offering potential targets for therapeutic intervention such as Cst7 and Ctsd in bone marrow-derived myeloid cells.

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