Zhang Weidong, Ding Fan, Rong Xing, Ren Qinghua, Hasegawa Tomoka, Liu Hongrui, Li Minqi
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.
Aging Cell. 2025 Feb;24(2):e14374. doi: 10.1111/acel.14374. Epub 2024 Oct 16.
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.
阿尔茨海默病（AD）患者比同龄认知正常的受试者遭受更严重的骨质流失。H型血管与骨稳态密切相关。然而，很少有研究关注骨血管改变及其在AD相关骨质流失中的作用。在本研究中，使用APP/PS1小鼠（4个月和8个月大）和年龄匹配的野生型小鼠来评估骨血管改变及其在AD相关骨质流失中的作用。利用透射电子显微镜、免疫荧光染色和iGPS 1.0软件数据库来研究分子机制。使用线粒体分裂抑制剂（Mdivi-1）和GSK-3β抑制剂（LiCl）来挽救H型血管损伤并验证分子机制。我们的结果显示，APP/PS1小鼠在衰老过程中表现出更严重的骨血管损伤和骨质流失。骨血管损伤，尤其是H型血管的损伤，伴随着APP/PS1小鼠血管化骨生成受损。进一步研究表明，β-淀粉样蛋白（Aβ）促进血管内皮细胞（ECs）凋亡并导致H型血管损伤。机制上，发现Aβ诱导的过度线粒体分裂对于ECs凋亡至关重要。GSK-3β被确定为Aβ诱导的过度线粒体分裂和骨质流失的关键调控靶点。这些发现表明，Aβ诱导的过度线粒体分裂驱动H型血管损伤，导致APP/PS1小鼠骨质流失加剧，GSK-3β抑制剂成为一种潜在的治疗策略。
