Patients with Alzheimer’s disease (AD) often have lower bone mass than healthy individuals. However, the mechanisms underlying this change remain elusive. Previously, we found that Tg2576 mice, an AD animal model that ubiquitously expresses Swedish mutant amyloid precursor protein (APP_swe), shows osteoporotic changes, reduced bone formation, and increased bone resorption. To understand how bone deficits develop in Tg2576 mice, we used a multiplex antibody array to screen for serum proteins that are altered in Tg2576 mice and identified hepcidin, a master regulator of iron homeostasis. We further investigated hepcidin’s function in bone homeostasis and found that hepcidin levels were increased not only in the serum but also in the liver, muscle, and osteoblast (OB) lineage cells in Tg2576 mice at both the mRNA and protein levels. We then generated mice selectively expressing hepcidin in hepatocytes or OB lineage cells, which showed trabecular bone loss and increased osteoclast (OC)-mediated bone resorption. Further cell studies suggested that hepcidin increased OC precursor proliferation and differentiation by downregulating ferroportin (FPN) expression and increasing intracellular iron levels. In OB lineage cells, APP_swe enhanced hepcidin expression by inducing ER stress and increasing OC formation, in part through hepcidin. Together, these results suggest that increased hepcidin expression in hepatocytes and OB lineage cells in Tg2576 mice contributes to enhanced osteoclastogenesis and trabecular bone loss, identifying the hepcidin-FPN-iron axis as a potential therapeutic target to prevent AD-associated bone loss.

阿尔茨海默病 (AD) 患者的骨量通常低于健康人。然而，这种变化背后的机制仍然难以捉摸。此前，我们发现 Tg2576 小鼠（一种普遍表达瑞典突变淀粉样前体蛋白（APP _swe ）的 AD 动物模型）表现出骨质疏松变化、骨形成减少和骨吸收增加。为了了解 Tg2576 小鼠骨缺陷如何发展，我们使用多重抗体阵列筛选 Tg2576 小鼠中发生改变的血清蛋白，并鉴定出铁调素（铁稳态的主要调节剂）。我们进一步研究了铁调素在骨稳态中的功能，发现铁调素水平不仅在血清中增加，而且在 Tg2576 小鼠的肝脏、肌肉和成骨细胞 (OB) 谱系细胞中的 mRNA 和蛋白质水平均增加。然后，我们培育了在肝细胞或 OB 谱系细胞中选择性表达铁调素的小鼠，其表现出小梁骨丢失和破骨细胞 (OC) 介导的骨吸收增加。进一步的细胞研究表明，hepcidin 通过下调铁转运蛋白 (FPN) 表达和增加细胞内铁水平来增加 OC 前体增殖和分化。在 OB 谱系细胞中，APP _swe通过诱导 ER 应激和增加 OC 形成（部分通过铁调素）来增强铁调素表达。总之，这些结果表明，Tg2576 小鼠肝细胞和 OB 谱系细胞中铁调素表达的增加有助于增强破骨细胞生成和小梁骨丢失，将铁调素-FPN-铁轴确定为预防 AD 相关骨丢失的潜在治疗靶点。