Amyloid-RAGE Signaling in Bone Remodeling

描述（由申请人提供）： 阿尔茨海默病（AD）是一种严重的神经退行性疾病，约有10%的65岁以上的老年人患有AD，其特征是大脑皮层和脑血管A2沉积、神经元缠结、慢性炎症和神经元丢失。骨质疏松症是另一种多因素疾病，其特征在于骨矿物质密度（BMD）低和骨组织微结构恶化。AD和骨质疏松症都是与高龄密切相关的常见慢性退行性疾病。这两种疾病的特征在于进行性组织损失，并且在很大程度上被视为具有不同局部病理限制的完全独立的疾病。这两种疾病都是多因素的，主要是多基因疾病，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激素缺乏，这些都起着重要的致病作用。虽然不被称为AD的主要并发症之一，但骨质疏松症和骨折率增加在AD患者中常见。越来越多的临床和流行病学研究证据支持这两种疾病存在一定程度的共病。然而，在文献中很少有研究涉及这个问题的机制，这是我们研究的长期目标。 淀粉样蛋白2肽（A2）是AD患者脑内淀粉样斑块的主要成分，由分泌酶对淀粉样前体蛋白（APP）进行蛋白水解加工而成。A2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，而且在许多非神经元细胞中表达，包括成骨细胞（OB）、破骨细胞（OC）和骨髓巨噬细胞（BMSCs）。然而，APP和/或A2在骨重建中的功能在很大程度上仍不清楚，这是我们研究的主要焦点。 我们的初步研究为APP和Abeta参与骨重建提供了证据。本申请的目的是确定APP/A2是否通过其受体β 2（晚期糖基化终产物受体）以年龄依赖性方式调节骨重塑的关键因素。该研究结果将提供APP-A2-A2轴和AD相关骨丢失之间的联系，确定APP和A2的新生物学功能，并揭示OC和OB分化，功能及其耦合的新机制。

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.