Amyloid-RAGE Signaling in Bone Remodeling

描述(由申请人提供)： 摘要阿尔茨海默病(AD)是一种最可怕的神经退行性疾病，在65岁以上的所有人中有10%受到影响，其特征是皮质和脑血管A2沉积，神经原纤维缠结，慢性炎症和神经元丢失。骨质疏松症是另一种多因素疾病，以低骨密度(BMD)和骨组织微结构恶化为特征。阿尔茨海默病和骨质疏松症都是常见的慢性退行性疾病，与老年密切相关。这两种疾病都以进行性组织丢失为特征，很大程度上被视为完全独立的疾病，具有不同的局部病理限制。这两种疾病都是多因素多基因疾病，涉及易感基因、衰老和环境因素作为致病机制。这两种疾病都涉及慢性炎症过程和荷尔蒙缺乏，这些都起着重要的致病作用。虽然不被认为是AD的主要并发症之一，但骨质疏松和骨折发生率增加在AD患者中很常见。来自临床和流行病学研究的越来越多的证据支持这两种疾病在一定程度上共病。然而，文献中很少有研究探讨这一问题的潜在机制，这是我们研究的长期目标。淀粉样蛋白2-肽(A_2)是阿尔茨海默病(AD)脑内淀粉样斑块的主要成分，是通过分泌酶活性对淀粉样前体蛋白(APP)进行蛋白分解的产物。A2的产生增加被认为是AD的主要原因。AP是一种跨膜蛋白，不仅在脑/神经元中表达，而且在许多非神经细胞中也有表达，包括成骨细胞(OBS)、破骨细胞(OCS)和骨髓巨噬细胞(BMMS)。然而，APP和/或A2在骨重建中的作用仍然很不清楚，这是我们研究的一个主要重点。我们的初步研究为APP和Abeta参与骨重建提供了证据。这项应用的目的是确定APP/A2是否通过其受体RAGE(晚期糖基化终产物受体)在以年龄依赖的方式调节骨重建方面是一个关键因素。这一研究结果将提供APP-A2-RAGE轴与AD相关性骨丢失之间的联系，鉴定APP和A2的新的生物学功能，并揭示OC和OB分化、功能及其偶联的新机制。 公共卫生相关性： 本研究旨在探讨APP(淀粉样前体蛋白)和A2(APP切割产物，含40-42个氨基酸)在病理和生理条件下调节骨重建的作用。它关系到我们对骨质疏松症和阿尔茨海默病(AD)发病机制的理解。AD是导致痴呆症的最常见原因，影响着多达500万美国人，其中许多人是退伍军人。骨质疏松症是另一种慢性退行性疾病，影响包括退伍军人在内的许多老年人。这两种疾病都严重影响了老年退伍军人的生活质量，但缺乏治愈的治疗方法。我们希望拟议的研究将为我们理解这两种疾病的发病机制提供有用的信息，这两种疾病与VA的研究目标高度相关。

DESCRIPTION (provided by applicant): Abstract Alzheimer's disease (AD), one of the most dreaded neurodegenerative disorders that affects 10% of all people over 65 years of age, is characterized by cortical and cerebrovascular A2 deposits, neurofibrillary tangles, chronic inflammation, and neuronal loss. Osteoporosis, another multifactoral disorder, is characterized by low bone mineral density (BMD) and microarchitectural deterioration of bone tissue. Both AD and osteoporosis are common chronic degenerative disorders strongly associated with advanced age. Both disorders are characterized by progressive tissue loss and are largely seen as completely independent diseases with different local restrictions of pathology. Both disorders are multifactoral mostly polygenetic diseases, involving susceptibility genes, ageing, and environmental factors as pathogenic mechanisms. Both disorders involve chronic inflammatory processes and hormonal deficiencies that play important pathogenic roles. Though not referred to as one of the major complications of AD, osteoporosis and increased bone fracture rates are commonly observed in patients with AD. Increasing evidence from clinical and epidemiological studies supports a degree of comorbidity of both disorders. However, very few studies are available in the literature that has addressed mechanisms underlying this problem, which is a long term goal of our research. Amyloid 2-peptide (A2), a major component of amyloid plaques in the brain of AD, is derived from proteolytic processing of APP (amyloid precursor protein) by secretase activities. Increased A2 production is believed to be a major cause of AD. AP, a transmembrane protein, is expressed not only in the brain/neurons, but also in many non- neuronal cells, including osteoblasts (OBs), osteoclasts (OCs), and bone marrow macrophages (BMMs). However, the function of APP and/or A2 in bone remodeling remains largely unclear, which is a major focus of our study. Our pilot studies have provided evidence for the involvement of APP and Abeta in bone remodeling. This application has the goal of determining whether APP/A2, via its receptor RAGE (receptor for advanced glycation endproduct), is a critical factor in regulating bone remodeling in an age dependent manner. The results from this proposal will provide a link between the APP-A2-RAGE axis and AD-associated bone loss, identify a new biological function of APP and A2, and reveal a new mechanism underlying OC and OB differentiation, function, and their coupling. PUBLIC HEALTH RELEVANCE: This proposal is to investigate functions of APP (amyloid precursor protein) and A2 (a cleavage product of APP with 40-42 amino acids) in regulating bone remodeling at both pathological and physiological conditions. It is relevant to our understanding of the pathogenesis of osteoporosis and Alzheimer's disorders (AD). AD, the most common cause of dementia, affects as many as 5 million Americans, and many of them are veterans. Osteoporosis, another chronic degenerative disorder, affects many aged people including veterans. Both disorders severely affect quality of life of aged veterans, but there is lack of cure treatment. It is our hope that the proposed research will provide useful information for our understanding of the pathogenesis of both disorders, which are highly relevant to the Research Objectives of VA.