Proteoglycans/Glycosaminoglycans in APP Transgenic Mice

APP 转基因小鼠中的蛋白聚糖/糖胺聚糖

• 批准号: 6786446
• 负责人: ALAN D. SNOW
• 金额: $ 52.08万
• 依托单位: PROTEOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2006-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6786446
• 关键词: Alzheimer' s disease; amyloid proteins; blood chemistry; disease /disorder model; gel filtration chromatography; gene expression; genetically modified animals; heparan sulfate; high voltage electrophoresis; human tissue; ion exchange chromatography; laboratory mouse; mucopolysaccharides; northern blottings; pathologic process; polymerase chain reaction; protein localization; proteoglycan; western blottings

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a degenerative brain disorders characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is the leading cause of dementia in the elderly, today affecting 4-5 million Americans, which is expected to double in incidence in the next 25 years. AD is characterized by the accumulation of insoluble fibrillar amyloid deposits containing the beta-amyloid protein (Abeta), either as extracellular amyloid plaques in the brain parenchyma or in blood vessel walls. Abeta amyloid formation, deposition and persistence in brain is believed to play a central role in AD pathogenesis by contributing to neuronal loss and memory dysfunction, and therefore has become a central target for the development of new drugs for the treatment of AD and related disorders. In AD, there is currently no cure or substantially effective treatment, and the patient usually dies within 3-10 years from disease onset. One of the most important amyloid co-components believed to play a primary role in the pathoqenesis of AD and other amyloid diseases are specific proteoqlycans (PGs) and glycosamino-qlycans (GAGs), especially those of the heparan sulfate (HS) class. Studies indicate that specific HSPGs accumulate early in AD brain and contribute to the pathoqenesis of Abeta amyloid formation by enhancinq Abeta deposition and persistence in brain. In both Down's syndrome and systemic AA amyIoidosis, it has been clearly demonstrated that HSPG formation and accumulation is an early event, prior to any detection of amyIoid (Abeta or AA amyIoid) deposition in tissues. Similarities between humans and mice with regards to the presence of specific HSPGs (including perlecan, aqrin, qlypican) in brain amyloid deposits make the APP transqenic mouse model a valuable tool to assess changes in HSPG deposition in brain and bioloqical fluids during initial and progressive phases of Abeta amyloid deposition and accumulation. Our data demonstrates that mice in general contain similar classes of GAGs in their plasma to their human counterparts (i.e. chondroitin-4-sulfate and heparan sulfate). In addition, our pilot data demonstrates that HS GAGs are elevated in CSF in AD versus normal aged controls, correlating with HSPG accumulation in AD brain. In this Phase I SBIR project we take advantage of important parallels between the APP transgenic mouse model and human AD (both in brain and biological fluids) to: 1) Identify the Specific HSPGs Upre, qulated in APP Transgenic Mouse Brain During Initiating and Progressive Phases of HSPG/Abeta Amyloid Deposition, and 2) Detect and Quantify Heparan Sulfate GAGs Derived from Biological Fluids of Human AD Patients and APP Transgenic Mice, and Determine Their Utility as a Diagnostic Marker for AD. These studies will lead to the identification and characterization of specific HSPGs/GAGs that are believed to play an early role in A( amyloid accumulation in AD and related disorders. In a future Phase II proposal, we intend to utilize important data generated from this Phase I project to isolate, fully characterize and prove that particular HSPGs in AD brain accelerate Abeta fibril formation and protect Abeta fibrils from protease degradation. We also intend to implement studies to prove that such an HSPG(s) is a relevant target for potential therapeutic intervention by testing a number of proprietary compounds developed at ProteoTech that block HSPG-Abeta interactions. In addition, we will more fully explore the use of plasma and CSF HS GAGs as diagnostic indicators of AD and its progression. It is clear from these projects that important commercial products (i.e. therapeutics and diagnostic) are anticipated to be developed for the treatment of AD and related disorders.

描述(申请人提供)：阿尔茨海默病(AD)是一种退行性脑疾病，临床特征是记忆、认知、推理、判断和情绪稳定性的进行性丧失，逐渐导致严重的精神恶化，最终导致死亡。AD是老年人痴呆症的主要原因，目前影响着400万至500万美国人，预计在未来25年内，AD的发病率将翻一番。AD的特征是含有β-淀粉样蛋白(Abeta)的不溶性纤维淀粉样沉积，在脑实质或血管壁上以细胞外淀粉样斑块的形式存在。Aβ淀粉样蛋白在脑内的形成、沉积和持续存在被认为在AD的发病机制中起核心作用，导致神经元丢失和记忆功能障碍，因此已成为治疗AD和相关疾病新药开发的中心靶点。在阿尔茨海默病中，目前没有治愈或基本有效的治疗方法，患者通常在发病后3-10年内死亡。 在AD和其他淀粉样疾病的发病机制中，最重要的淀粉样共组分之一是特异性蛋白多糖(PGs)和糖氨基多聚糖(GAG)，尤其是硫酸乙酰肝素(HS)类。研究表明，特定的HSPG在AD脑内早期积聚，并通过促进Aβ在脑内的沉积和持久性而参与Aβ淀粉样蛋白的形成。在唐氏综合征和系统性淀粉样变性中，已经清楚地证明HSPG的形成和积聚是在组织中检测到淀粉样蛋白(Abeta或AA淀粉样蛋白)沉积之前的早期事件。人类和小鼠在脑淀粉样蛋白沉积中存在特定的HSPG(包括perlecan，aqrin，qlypcan)方面的相似性使APP转基因小鼠模型成为评估Aβ淀粉样蛋白沉积和积累的初始和进展阶段脑和生物液中HSPG沉积变化的有价值的工具。我们的数据表明，一般来说，小鼠的血浆中含有与人类同类产品相似的GAG(即软骨素-4-硫酸盐和硫酸乙酰肝素)。此外，我们的实验数据表明，与正常老年对照组相比，AD患者脑脊液中HS-GAG水平升高，这与HSPG在AD脑中的积聚有关。在这个第一阶段的SBIR项目中，我们利用APP转基因小鼠模型和人类AD(在脑和生物液中)的重要相似性：1)鉴定APP转基因小鼠脑中在HSPG/Aβ淀粉样蛋白沉积的起始和进行期中表达的特异性HSPG UPRE；2)检测和定量来自人AD患者和APP转基因小鼠生物液的硫酸乙酰肝素GAG，并确定它们作为AD诊断标志物的有效性。这些研究将导致特定的HSPG/GAG的鉴定和表征，这些HSPG/GAG被认为在AD及相关疾病中的淀粉样蛋白积聚起早期作用。在未来的第二阶段计划中，我们打算利用这一第一阶段项目产生的重要数据来分离、充分表征和证明AD脑中特定的HSPG加速Abeta纤维的形成并保护Abeta纤维免受蛋白酶降解。我们还打算进行研究，通过测试ProteoTech开发的一些阻止HSPG-Abeta相互作用的专利化合物来证明这种HSPG(S)是潜在治疗干预的相关靶点。此外，我们将更充分地探索血浆和脑脊液HS GAG作为AD及其进展的诊断指标的应用。从这些项目中可以清楚地看出，预计将开发用于治疗阿尔茨海默病和相关疾病的重要商业产品(即治疗和诊断)。