2. Academic Validation
  3. Aβ impairs bone vascular homeostasis in APP/PS1 mice via disrupting the mitochondrial fission-efferocytosis axis in macrophages

Aβ impairs bone vascular homeostasis in APP/PS1 mice via disrupting the mitochondrial fission-efferocytosis axis in macrophages

  • Int Immunopharmacol. 2025 Sep 10:165:115526. doi: 10.1016/j.intimp.2025.115526.
Ting Liu 1,  Weidong Zhang 2,  Wenzheng Bao 2,  Xiaorui Wang 2,  Fan Zhang 3,  Jie Guo 4,  Minqi Li 5
Affiliations

Affiliations

  • 1 Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China; Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, China.
  • 2 Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China.
  • 3 Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China; Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, China. Electronic address: zhfan@sdu.edu.cn.
  • 4 Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China; Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, China. Electronic address: kqgj@sdu.edu.cn.
  • 5 Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China; School of Clinical Medicine, Jining Medical University, Jining, China. Electronic address: liminqi@sdu.edu.cn.
PMID: 40934542 DOI: 10.1016/j.intimp.2025.115526
Abstract

Alzheimer's disease (AD) is associated with progressive bone loss, but the underlying mechanisms remain unclear. This study focused on how Amyloid-β (Aβ) disrupted bone vascular homeostasis by impairing macrophage efferocytosis in APP/PS1 mice. We found that Aβ accumulation in bone tissue impaired MerTK-mediated macrophage efferocytosis and promoted excessive accumulation of apoptotic endothelial cells (ECs). Mechanistically, Aβ triggered excessive mitochondrial fission via GSK-3β-mediated DRP1 phosphorylation, resulting in elevated Reactive Oxygen Species (ROS) and subsequent ADAM17 activation. ADAM17 cleaved MerTK, a critical efferocytosis receptor, impairing apoptotic cells (ACs) clearance. Pharmacological inhibition of GSK-3β (LiCl and TDZD-8) or mitochondrial fission (Mdivi-1) restored MerTK expression, improved efferocytosis, and reduced inflammatory cytokine release (such as TNF-α, IL-6), while enhancing vascular endothelial growth factors (VEGFs). In vivo, LiCl treatment ameliorated bone loss and vascular dysfunction in APP/PS1 mice. These findings revealed that Aβ disrupted the mitochondrial fission-efferocytosis axis in macrophages, contributing to AD-related bone pathology, and highlighted GSK-3β as a potential therapeutic target for preserving bone vascular homeostasis in AD.

Keywords

ADAM17; Alzheimer's disease; Bone loss; Efferocytosis; GSK-3β; MerTK; Mitochondrial fission.

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