FAD 4T Mouse Model Reflects Alzheimer’s Disease Pathobiology in the Bone Marrow-Brain Axis

Introduction: Alzheimer's disease (AD) and Osteoporosis (OP) are two concomitant degenerative diseases in the aged population. However, there is unclear the relationship between AD and OP.Methods: We developed an AD model, and examined changes of bone marrow and brain immune cells in different ages of mice by flow cytometry, single-cell sequencing analysis and immunofluorescence staining.Results: FAD4T mice exhibit typical AD symptoms, and accompanied by bone loss. FAD4T mice revealed myeloid-biased bone marrow output and decreased mitochondrial activity in hematopoietic stem cells and myeloid progenitor cells. Coupregulation of AD-related genes such as Cst7 and Ctsd in both bone marrow and brain macrophages, and both the Ccl4-Ccr5 and Ccl3-Ccr5 axes are highly enriched between macrophages and microglia.Discussion: Bone marrow-derived macrophages shape the inflammatory microenvironment in the brain during the progression of AD. It is possible that bone alteration during aging contributes to AD progression via the bone marrow-brain axis. Funding: This study was performed with the support of the National Natural Science Foundation of China (82002339, 81820108020), Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System (BJ1-9000-22-4002), Shanghai Municipal Hospital Orthopedic Specialist Alliance, Shanghai Municipal Health Commission key priority discipline project; Shanghai Spinal Disease and Trauma Orthopedics Research Center, and the Natural Science foundation of Jiangsu Province (BK20221155).Declaration of Interest: The authors declare no commercial or financial potential conflict of interest concerning the research, authorship, and/or publication of this article.Ethical Approval: The protocol (Animal Protocol No. GPTAP014) and any amendments or procedures involving the care and use of animals in this study were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of GemPharmatech Co., Ltd. prior to conducting any experiments. During the study, the care and use of animals were conducted in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).