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

 描述(申请人提供)：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。阿尔茨海默病(AD)是一种最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在一定程度上并存。然而，很少有研究可以解决他们之间的关系。这项建议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AD和骨质疏松症/骨量减少的共同分母。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，我们推测APP/A可能与AD相关的骨骼缺陷有关。我们以Tg2576小鼠为模型，观察了该动物模型的年龄依赖性骨质疏松骨缺失情况。通过新建立的条件性/细胞型APPsWE转基因小鼠模型，我们发现APPsWE在调节成骨细胞(OB)介导骨形成和破骨细胞(OC)介导骨吸收中发挥重要作用。然而，潜在的机制尚不清楚。在这项提案中，我们将解决这个问题。我们希望这项研究的结果不仅可以提供AD与骨质疏松/骨质减少之间的潜在联系，还可以发现APP未知的功能，并揭示这两种疾病的新的病理机制。

 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.