Aβ ‐induced excessive mitochondrial fission drives type H blood vessels injury to aggravate bone loss in APP/PS1 mice with Alzheimer's diseases

Abstract Alzheimer's diseases (AD) patients suffer from more serious bone loss than cognitively normal subjects at the same age. Type H blood vessels were tightly associated with bone homeostasis. However, few studies have concentrated on bone vascular alteration and its role in AD‐related bone loss. In this study, APP/PS1 mice (4‐ and 8‐month‐old) and age‐matched wild‐type mice were used to assess the bone vascular alteration and its role in AD‐related bone loss. Transmission electron microscopy, immunofluorescence staining and iGPS 1.0 software database were utilized to investigate the molecular mechanism. Mitochondrial division inhibitor (Mdivi‐1) and GSK‐3β inhibitor (LiCl) were used to rescue type H blood vessels injury and verify the molecular mechanism. Our results revealed that APP/PS1 mice exhibited more serious bone blood vessels injury and bone loss during ageing. The bone blood vessel injury, especially in type H blood vessels, was accompanied by impaired vascularized osteogenesis in APP/PS1 mice. Further exploration indicated that beta‐amyloid (Aβ) promoted the apoptosis of vascular endothelial cells (ECs) and resulted in type H blood vessels injury. Mechanistically, Aβ‐induced excessive mitochondrial fission was found to be essential for the apoptosis of ECs. GSK‐3β was identified as a key regulatory target of Aβ‐induced excessive mitochondrial fission and bone loss. The findings delineated that Aβ‐induced excessive mitochondrial fission drives type H blood vessels injury, leading to aggravate bone loss in APP/PS1 mice and GSK‐3β inhibitor emerges as a potential therapeutic strategy.