Institute of Molecular Medicine & Genetics and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA; Department of Rheumatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R., China.
J Bone Miner Res. 2013 Oct;28(10):2122-35. doi: 10.1002/jbmr.1954.
Reduced bone mineral density and hip fracture are frequently observed in patients with Alzheimer's disease (AD). However, mechanisms underlying their association remain poorly understood. Amyloid precursor protein (APP) is a transmembrane protein that is ubiquitously expressed in bone marrow stromal cells (BMSCs), osteoblasts (OBs), macrophages (BMMs), and osteoclasts (OCs). Mutations in the APP gene identified in early-onset AD patients are believed to cause AD. But little is known about APP's role in bone remodeling. Here, we present evidence for Swedish mutant APP (APPswe) in suppression of OB differentiation and function in culture and in mouse. APP expression in BMSCs increases during aging. Ubiquitous expression of APPswe in young adult Tg2576 transgenic mice (under the control of a prion promoter) recaptured skeletal "aging-like" deficits, including decreased OB genesis and bone formation, increased adipogenesis and bone marrow fat, and enhanced OC genesis and bone resorption. Remarkably, selective expression of APPswe in mature OB-lineage cells in TgAPPswe-Ocn mice (under the control of osteocalcin [Ocn] promoter-driven Cre) also decreased OB genesis and increased OC formation, resulting in a trabecular bone loss. These results thus suggest a cell-autonomous role for APPswe in suppressing OB formation and function, but a nonautonomous effect on OC genesis. Notably, increased adipogenesis and elevated bone marrow fat were detected in young adult Tg2576 mice, but not in TgAPPswe-Ocn mice, implying that APPswe in BMSCs and/or multicell types in bone marrow promotes bone marrow adipogenesis. Intriguingly, the skeletal aging-like deficits in young adult Tg2576 mice were prevented by treatment with N-acetyl-L-cysteine (NAC), an antioxidant, suggesting that reactive oxygen species (ROS) may underlie APPswe-induced osteoporotic deficits. Taken together, these results demonstrate a role for APPswe in suppressing OB differentiation and bone formation, implicate APPswe as a detrimental factor for AD-associated osteoporotic deficit, and reveal a potential clinical value of NAC in the treatment of osteoporotic deficits. © 2013 American Society for Bone and Mineral Research.
阿尔茨海默病（AD）患者常出现骨密度降低和髋部骨折。然而，其相关机制仍不清楚。淀粉样前体蛋白（APP）是一种在骨髓基质细胞（BMSCs）、成骨细胞（OBs）、巨噬细胞（BMMs）和破骨细胞（OCs）中广泛表达的跨膜蛋白。早发性 AD 患者中发现的 APP 基因突变被认为会导致 AD。但 APP 在骨重塑中的作用知之甚少。在这里，我们提供了 APP 突变（APPswe）在体外和小鼠中抑制 OB 分化和功能的证据。BMSCs 中的 APP 表达随年龄增长而增加。年轻成年 Tg2576 转基因小鼠（在朊病毒启动子的控制下）中广泛表达 APPswe，重现了骨骼“衰老样”缺陷，包括 OB 生成和骨形成减少、脂肪生成和骨髓脂肪增加、OC 生成和骨吸收增强。值得注意的是，在 TgAPPswe-Ocn 小鼠（在骨钙素 [Ocn] 启动子驱动的 Cre 控制下）中成骨细胞谱系细胞中选择性表达 APPswe 也会减少 OB 生成并增加 OC 形成，导致小梁骨丢失。因此，这些结果表明 APPswe 在抑制 OB 形成和功能方面具有细胞自主作用，但对 OC 生成具有非自主作用。值得注意的是，在年轻成年 Tg2576 小鼠中检测到脂肪生成增加和骨髓脂肪升高，但在 TgAPPswe-Ocn 小鼠中未检测到，这表明 BMSCs 中的 APPswe 和/或骨髓中的多细胞类型促进骨髓脂肪生成。有趣的是，抗氧化剂 N-乙酰-L-半胱氨酸（NAC）的治疗可预防年轻成年 Tg2576 小鼠的骨骼衰老样缺陷，表明活性氧（ROS）可能是 APPswe 诱导的骨质疏松缺陷的基础。综上所述，这些结果表明 APPswe 在抑制 OB 分化和骨形成中起作用，表明 APPswe 是 AD 相关骨质疏松缺陷的有害因素，并揭示了 NAC 在骨质疏松缺陷治疗中的潜在临床价值。
