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骨骼退行性疾病，以骨量减少和骨组织微结构恶化为特征。其原因是破骨细胞(OC)介导的骨吸收增加和/或成骨细胞(OB)介导的骨形成减少。阿尔茨海默病(AD)是一种常见的神经退行性疾病，伴有认知性痴呆。有趣的是，与同龄正常人群相比，AD患者往往具有较低的骨密度和较高的髋部骨折发生率。几个新发现的AD风险基因/位点编码对破骨细胞激活和/或骨量动态平衡至关重要的蛋白质。因此，来自临床和遗传学研究的越来越多的证据支持这两种疾病之间存在一定程度的联系。然而，很少有研究可用于解决潜在的机制。这项提案的目标是确定瑞典突变的淀粉样前体蛋白(APPsWE)是否以及如何作为骨质疏松的风险因素。APP是一种普遍表达的跨膜蛋白。它的切割产物A被认为是早发性和晚发性AD的主要罪魁祸首。因此，我们探索了APPsWE在AD相关的小鼠骨骼缺陷中的可能贡献。Tg2576小鼠在Prion启动子的控制下表达APPsWE，并在老年(10个月龄)出现AD相关的神经病理缺陷。值得注意的是，我们的初步研究显示，在这个AD动物模型中，存在年龄相关性的骨质疏松缺陷，包括年轻时骨小梁减少，老年时骨组织恶化。骨量减少与成骨细胞性骨形成减少和破骨细胞性骨吸收增加有关。骨质结构恶化之前是破骨细胞性骨吸收受损。为了研究潜在的机制，我们培育了一只转基因小鼠，能够在OBS和OCS中实现APPsWE的细胞类型特异性表达。我们的结果表明，APPswe在抑制OB介导的骨形成和调节OC激活方面发挥着细胞自主作用。这些结果揭示了APPsWE破坏骨骼动态平衡的潜在新的细胞机制。然而，潜在的分子机制仍不清楚。在这项提案中，我们将解决这个问题。这项研究不仅将提供AD与骨骼缺陷之间的潜在联系，而且还将确定APP和APPsWE未知的功能，并揭示骨质疏松症和AD的新的病理生理机制，这两种慢性退行性疾病都会影响许多退伍军人的生活质量，并与退伍军人退伍军人战略目标高度相关。

 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.