APP/ABeta chemistry in transgenic/familial/sporadic AD

转基因/家族性/散发性 AD 中的 APP/Aβ 化学

• 批准号: 6967385
• 负责人: ALEX E ROHER
• 金额: $ 29.83万
• 依托单位: BANNER SUN HEALTH RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6967385
• 关键词: Alzheimer' s disease; aging; amyloid proteins; amyloidosis; apolipoprotein E; disease /disorder model; genetic disorder; genetically modified animals; genotype; high performance liquid chromatography; histochemistry /cytochemistry; immunologic assay /test; laboratory mouse; mass spectrometry; matrix assisted laser desorption ionization; neuropathology; neurophysiology; nonhuman therapy evaluation; phenotype; presenilin; protein localization; protein purification; protein structure function; surface enhanced laser desorption ionization; transforming growth factors

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a dementia that affects 4 million elderly individuals in the USA. This devastating neurodegenerative disorder strikes 4% of individuals at 65 years of age and as many as 40% of those at age 85 at a cost of about 80 billion dollars annually. Due to an impressive increase in longevity there is a projected tripling in the number of AD dementia cases by the year 2050. Therefore, there is an urgent need for effective therapeutic interventions that may prevent AD or delay the age of onset or alter the course of this dementia. The creation of transgenic (tg) mice expressing human AD genes has provided vital tools to investigate both the pathogenesis and treatment of this dementia. Our goal is to better understand the strengths and limitations of tg mice models by determining the degree of biochemical similarities existing between tg animal amyloid and that deposited in human AD patients. Amyloid produced in several tg animal constructs that express mutations in the large amyloid precursor molecule and the key proteolytic processing enzyme presenilin will be purified and chemically characterized to determine composition and structure in comparison to human sporadic and familial AD patient amyloid. Soluble and deposited amyloid remaining after anti-Abeta immunization of tg mice and human AD patients will be examined using the same chemical techniques to assess the effects of immunization on amyloid dynamics and toxicity. This study will aid in the accurate interpretation of tg mouse experimental results and will help elucidate at the molecular level the direct and indirect effects of anti-Abeta immunization. A complete understanding of the tg mice phenotypes and responses to experimental therapeutic interventions will enable new results to be applied to human AD patients with minimum delay and maximum confidence in efficacy and safety.

描述（由申请人提供）：阿尔茨海默病（AD）是一种影响美国400万老年人的痴呆症。这种毁灭性的神经退行性疾病在65岁的人中占4%，在85岁的人中占40%，每年花费约800亿美元。由于寿命的显著增加，预计到2050年AD痴呆病例的数量将增加两倍。因此，迫切需要有效的治疗干预措施，可以预防AD或延迟发病年龄或改变这种痴呆症的病程。表达人类AD基因的转基因（tg）小鼠的建立为研究这种痴呆的发病机制和治疗提供了重要工具。我们的目标是更好地了解tg小鼠模型的优势和局限性，通过确定存在的生化相似性之间的程度tg动物淀粉样蛋白和沉积在人类AD患者。将纯化在几种tg动物构建体中产生的淀粉样蛋白，所述构建体表达大淀粉样蛋白前体分子和关键蛋白水解加工酶早老素中的突变，并进行化学表征，以确定与人散发性和家族性AD患者淀粉样蛋白相比的组成和结构。将使用相同的化学技术检查tg小鼠和人AD患者的抗Abeta免疫后剩余的可溶性和沉积的淀粉样蛋白，以评估免疫对淀粉样蛋白动力学和毒性的影响。这项研究将有助于准确解释tg小鼠实验结果，并有助于在分子水平上阐明抗Abeta免疫的直接和间接影响。对tg小鼠表型和对实验性治疗干预的反应的全面了解将使新的结果能够以最小的延迟和最大的疗效和安全性置信度应用于人类AD患者。