APP as a common denominator for Alzheimer's disease and osteoporosis

APP 是阿尔茨海默病和骨质疏松症的共同点

• 批准号: 9607371
• 负责人: WEN-CHENG XIONG
• 金额: $ 28.61万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9607371
• 关键词: APP; common; denominator; Alzheimer; disease

 DESCRIPTION (provided by applicant): Osteoporosis, a common skeletal degenerative disorder, is characterized by decrease of bone- mass and micro-architectural deterioration of bone tissue. Alzheimer's disease (AD) is a most common neurodegenerative disorder with cognitive dementia. Intriguingly, AD patients frequently have lower bone mineral density and higher rate of hip fracture, compared with the same age normal population. Several newly identified AD risk genes/loci encode proteins critical for osteoclastic activation and/or bone-mass homeostasis. Increasing evidence from clinical and genetic studies thus supports a degree of co-morbidity of both disorders. However, very few studies are available to address their relationship. The goal of this proposal is to determine if and how the Swedish mutant amyloid precursor protein (APPswe) acts as a common denominator for AD and osteoporosis/osteopenia. APP is a ubiquitously expressed transmembrane protein. Its cleavage product, A, is believed to be a major culprit for both early- and late-onset AD. We thus speculate that APP/A may contribute to the AD-associated skeletal deficits. By use of Tg2576 mice, a well-characterized AD animal model that ubiquitously expresses APPswe under the control of prion promoter, we observed age-dependent osteoporotic bone deficits in this animal model. By use of newly generated conditional/cell type specific APPswe transgenic mouse models, we found that APPswe plays important roles in regulating osteoblast (OB)-mediated bone formation and osteoclast (OC)-mediated bone resorption. However, the underlying mechanisms are unclear. In this proposal, we will address this issue. It is our hope that the results from this research may not only provide a potential link between AD and osteoporosis/osteopenia, but also identify unrecognized functions of APP and reveal new pathological mechanisms underlying both disorders.

 描述（由申请人提供）：骨质疏松症是一种常见的骨骼退行性疾病，其特征在于骨量减少和骨组织的微结构退化。阿尔茨海默病（Alzheimer's disease，AD）是一种常见的神经退行性疾病，以认知性痴呆（cognitive dementia）为特征。有趣的是，与同龄正常人群相比，AD患者通常具有较低的骨矿物质密度和较高的髋部骨折率。几个新发现的AD风险基因/位点编码的蛋白质对骨细胞活化和/或骨量稳态至关重要。因此，越来越多的临床和遗传学研究证据支持这两种疾病的共病程度。然而，很少有研究可以解决它们之间的关系。本提案的目的是确定瑞典突变淀粉样前体蛋白（APPswe）是否以及如何作为AD和骨质疏松/骨质减少的共同标准。APP是一种普遍表达的跨膜蛋白。其裂解产物A β被认为是早发性和迟发性AD的主要罪魁祸首。因此，我们推测APP/A β可能有助于AD相关的骨骼缺陷。通过使用Tg 2576小鼠，一种充分表征的AD动物模型，其在朊病毒启动子的控制下普遍表达APPswe，我们在该动物模型中观察到年龄依赖性骨质疏松性骨缺损。利用新近建立的条件性/细胞类型特异性APPswe转基因小鼠模型，我们发现APPswe在调节成骨细胞（OB）介导的骨形成和破骨细胞（OC）介导的骨吸收中起重要作用。然而，其潜在机制尚不清楚。在本提案中，我们将处理这一问题。我们希望这项研究的结果不仅可以提供AD和骨质疏松/骨量减少之间的潜在联系，而且还可以确定APP未被识别的功能，并揭示这两种疾病的新的病理机制。