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

基本信息

批准号：
9903240
负责人：
WEN-CHENG XIONG
金额：
$ 40万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903240
关键词：
Address Age Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Precursor Animal Disease Models Animal Model Architecture Attenuated Bone Density Bone Marrow Bone Resorption Bone Tissue Bone structure Cell Lineage Cell surface Cells Clinical Research Cognitive Degenerative Disorder Dementia Deterioration Disease Family Genes Genetic study Goals Hamsters Hip Fractures Homeostasis Impairment Integral Membrane Protein Iron Iron Chelation Knowledge Late Onset Alzheimer Disease Lead Ligands Link Mediating Molecular Mus Mutation Neurodegenerative Disorders Osteoblasts Osteoclasts Osteogenesis Osteopenia Osteoporosis Osteoporotic Pathologic Play Population Presenile Alzheimer Dementia Prions Proteins Proteolysis Research Role Signal Transduction Swedish mutation Testing Tg2576 Transgenic Mice WNT Signaling Pathway age related aged biomarker development bone bone loss bone mass cell type comorbidity genomic locus hepcidin in vivo macrophage member mouse model mutant novel osteoblast differentiation osteoporotic bone promoter protein function public health relevance receptor risk variant selective expression skeletal substantia spongiosa young adult

项目摘要

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（由适用提供）：骨质疏松症（一种常见的骨骼退行性疾病）的特征是骨骼组织的减少和骨组织的微构造恶化。阿尔茨海默氏病（AD）是具有认知痴呆症的最常见神经退行性疾病。有趣的是，与同一年龄正常人群相比，AD患者经常具有较低的骨矿物质密度和较高的髋部骨折率。几个新鉴定的AD风险基因/基因座编码对整骨激活和/或骨质量稳态至关重要的蛋白质。因此，来自临床和遗传研究的越来越多的证据支持两种疾病的合并症程度。但是，很少有研究可以解决他们的关系。该提案的目的是确定瑞典突变淀粉样蛋白（APPSWE）是否以及如何作为AD和骨质疏松症/骨质骨减少症的共同点。 APP是一种普遍表达的跨膜蛋白。它的乳沟产品A被认为是早期和晚期广告的主要罪魁祸首。因此，我们推测应用程序/A可能有助于与广告相关的骨骼定义。通过使用TG2576小鼠，这是一种在Prime启动子的控制下无处不在表达AppSwe的特征良好的AD动物模型，我们观察到该动物模型中定义了依赖年龄的骨质疏松骨。通过使用新生成的条件/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）介导的骨形成和骨细胞（OC）介导的骨骼分辨率方面起着重要作用。但是，基本机制尚不清楚。在此提案中，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和骨质疏松症/骨质骨减少症之间的潜在联系，而且还可以确定APP的未认识功能，并揭示了这两种疾病的新病理机制。