Delineating conformational variants of the Abeta peptide

描述 Abeta 肽的构象变体

• 批准号: 8525300
• 负责人: Joel Watts
• 金额: $ 9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525300
• 关键词: Adopted; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Biological; Biological Assay; Brain; Cause of Death; Cell Line; Cell model; Cells; Dementia; Deposition; Development; Digestion; Disease; Event; Exhibits; FDA approved; Genes; Human; In Vitro; Individual; Lead; Mentors; Methods; Modeling; Molecular Conformation; Mus; Mutation; Nerve Degeneration; Neuraxis; Neurofibrillary Tangles; Neuroglia; Neurons; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phase; Polymers; Preparation; Prion Diseases; Prions; Procedures; Process; Production; Property; Research; Resistance; Sampling; Senile Plaques; Structure; System; Techniques; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Variant; age related; aging brain; aging population; base; brain cell; disease phenotype; economic cost; effective therapy; familial Alzheimer disease; in vitro Assay; in vivo; mouse model; mutant; neurofibrillary tangle formation; novel; polymerization; presenilin; prion-like; research study; response; social; stem cell technology; success; tau Proteins; tau aggregation; tool

DESCRIPTION (provided by applicant): Over 5 million Americans currently suffer from Alzheimer's disease (AD), and this number is projected to increase with an aging population. There are presently no FDA-approved drugs that halt or even slow the process of neurodegeneration in patients with AD, necessitating urgent action. AD is a progressive dementia caused by the accumulation of amyloid plaques containing A¿ peptide as well as neurofibrillary tangles (NFTs) harboring aggregated tau protein in the central nervous system. The initiating event in AD is thought to be the accumulation and aggregation of A¿ peptide in the brain, which ultimately leads to tau hyperphosphorylation and NFT formation. There is growing evidence that both A¿ and tau may possess several prion-like properties including the potential to be transmitted under certain experimental conditions. In addition, recent experiments have suggested that aggregated A¿ can adopt several different conformations or structures. In particular, fibrillar A¿ species derived from AD brains are thought to be distinct from fibrillar A structures generated by polymerization of synthetic A¿ peptide. This phenomenon is reminiscent of prion disease in which different conformations or 'strains' of the prion protein cause distinct disease phenotypes. However, it is currently unknown whether diverse A¿ strains or conformations can exist in the human brain. Interestingly, transgenic (Tg) mouse models of AD based on expression of mutant human amyloid precursor protein (APP) exhibit age- dependent A¿ deposition and amyloid plaque formation but do not develop NFTs. One possible explanation for the discrepancy between AD and Tg mouse brains is that fundamentally different A¿ strains are present. Understanding this problem is highly important for the development of novel A¿ -directed therapeutics since it is conceivable that compounds active against mouse brain-derived A¿ conformations will be inefficacious against human brain-derived A¿ strains, a problem that has been repeatedly encountered in prion disease. Thus, the objectives of this proposal are to develop methods for delineating and classifying the range of possible A¿ conformations in the brain as well as techniques for assaying the biological relevance of different A¿ strains. During two years of mentored postdoctoral studies (K99 phase) and three years of independent research (R00 phase), these experiments will determine whether different conformations of the A¿ peptide exist in the brains of Tg mice and AD patients. These studies are the necessary first steps towards the development of novel cell and animal models that more accurately recapitulate the important biological events in AD, and which may be more informative for developing and testing potential AD therapeutics.

描述(由申请人提供)：目前有超过500万美国人患有阿尔茨海默病(AD)，随着人口老龄化，这一数字预计还会增加。目前还没有FDA批准的药物来阻止甚至减缓AD患者的神经退化过程，因此需要采取紧急行动。AD是一种进行性痴呆，由中枢神经系统中含有A？肽的淀粉样斑块和含有聚集的tau蛋白的神经原纤维缠结(NFT)所致。AD的始发事件被认为是A？肽在脑内的积聚和聚集，最终导致tau过度磷酸化和NFT的形成。越来越多的证据表明，A？和tau都可能具有几种类似于Pron的性质，包括在某些实验条件下被传播的潜力。此外，最近的实验表明，聚集的A可以采用几种不同的构象或结构。特别是，来自AD大脑的纤维A？物种被认为与由合成A？肽聚合产生的纤维A？结构不同。这种现象让人联想到普恩病毒病，在这种疾病中，普恩蛋白的不同构象或‘菌株’会导致不同的疾病表型。然而，目前尚不清楚人类大脑中是否存在不同的A？菌株或构象。有趣的是，基于突变的人淀粉样前体蛋白(APP)表达的转基因(TG)AD小鼠模型显示出年龄相关的A？沉积和淀粉样斑块形成，但不会发生NFT。AD和TG小鼠大脑之间的差异的一个可能的解释是，存在着根本不同的A？菌株。了解这个问题对于开发新的A？导向疗法非常重要，因为可以想象，抗小鼠脑源性A？构象的活性化合物对人类脑源性A？菌株无效，这是在普恩病毒疾病中反复遇到的问题。因此，这项建议的目标是开发方法来描述和分类大脑中可能的A？构象范围，以及用于分析不同A？菌株的生物学相关性的技术。在两年的指导博士后研究(K99阶段)和三年的独立研究(R00阶段)中，这些实验将确定在TG小鼠和AD患者的大脑中是否存在不同构象的A？肽。这些研究是开发新的细胞和动物模型的必要的第一步，这些模型可以更准确地概括AD中的重要生物学事件，并可能为开发和测试潜在的AD治疗方法提供更多信息。