APPswe as a risk factor for osteoporosis

 描述（由申请人提供）： 摘要骨质疏松症是一种常见的以骨量减少和骨组织微结构破坏为特征的骨骼退行性疾病。其由破骨细胞（OC）介导的骨吸收增加和/或成骨细胞（OB）介导的骨形成减少引起。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之间存在一定程度的关联。然而，很少有研究可以解决潜在的机制。 这项提案的目的是确定瑞典突变淀粉样前体蛋白（APPswe）是否以及如何作为骨质疏松症的危险因素。APP是一种广泛表达的跨膜蛋白。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，我们探索了APPswe对小鼠中AD相关骨骼缺陷的可能贡献。Tg 2576小鼠在朊病毒启动子的控制下表达APPswe，并且在较大年龄（>10月龄）时发展AD相关的神经病理缺陷。值得注意的是，我们的初步研究揭示了该AD动物模型中的年龄依赖性骨质疏松缺陷，包括年轻成人年龄的骨小梁骨量减少和老年骨组织恶化。骨量减少与成骨细胞骨形成减少和骨吸收增加有关。骨结构恶化之前，受损的骨细胞骨吸收。为了研究潜在的机制，我们产生了一种转基因小鼠，其能够在OB和OC中细胞类型特异性表达APPswe。我们的研究结果表明，APPswe在抑制OB介导的骨形成和调节OC激活中起着细胞自主作用。这些结果揭示了APPswe破坏骨稳态的潜在新细胞机制。然而，潜在的分子机制仍不清楚。在本提案中，我们将处理这一问题。 这项研究不仅提供了AD和骨骼缺陷之间的潜在联系，而且还确定了APP和APPswe未被识别的功能，并揭示了骨质疏松症和AD的新的病理生理机制，这两种慢性退行性疾病影响许多退伍军人的生活质量，并与VA的战略目标高度相关。

 DESCRIPTION (provided by applicant): ABSTRACT Osteoporosis is a common skeletal degenerative disorder that is characterized by decrease of bone-mass and micro-architectural deterioration of bone tissue. It results from increased osteoclast (OC)-mediated bone resorption and/or reduced osteoblast (OB)-mediated bone formation. Alzheimer's disease (AD) is a 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 association of both disorders. However, very few studies are available to address the underlying mechanisms. The goal of this proposal is to determine if and how the Swedish mutant amyloid precursor protein (APPswe) acts as a risk factor for osteoporosis. 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 explored the possible contribution of APPswe to AD- associated skeletal deficits in mice. Tg2576 mice express APPswe under the control of prion promoter, and develop AD-relevant neuro-pathologic deficits at older age (>10 months old). Remarkably, our preliminary studies revealed age-dependent osteoporotic deficits in this AD animal model, including reduced trabecular bone-mass in young adult age and deteriorated bone tissue at older age. The reduced bone-mass was associated with a decrease in osteoblastic bone formation and an increase in osteoclastic bone resorption. The deteriorated bone structure was preceded by an impaired osteoclastic bone resorption. To investigate underlying mechanisms, we generated a transgenic mouse that enables cell-type specific expression of APPswe in OBs and OCs. Our results suggest that APPswe plays a cell autonomous role in suppressing OB-mediated bone formation and in regulating OC activation. These results uncovered potentially novel cellular mechanisms by which APPswe disrupts bone homeostasis. However, underlying molecular mechanisms remain unclear. In this proposal, we will address this issue. This research will not only provide a potential link between AD and skeletal deficits, but also identify unrecognized functions of APP and APPswe, and reveal new pathophysiological mechanisms underlying osteoporosis and AD, both chronic degenerative disorders affecting many veteran's quality of life and highly relevant to Strategic Objectives of VA.