Delineating conformational variants of the Abeta peptide

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），并且随着人口老龄化，这一数字预计会增加。目前还没有fda批准的药物可以阻止甚至减缓阿尔茨海默病患者神经退行性变的过程，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tau蛋白的神经原纤维缠结（nft）的积累引起。AD的起始事件被认为是A -肽在大脑中的积累和聚集，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朊病毒的特性，包括在某些实验条件下传播的潜力。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大脑的纤维状A¿物种被认为与合成A¿肽聚合产生的纤维状A结构不同。这种现象让人联想到朊病毒疾病，在这种疾病中，朊病毒蛋白的不同构象或“菌株”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，基于突变的人类淀粉样蛋白前体蛋白（APP）表达的AD转基因（Tg）小鼠模型表现出年龄依赖性A -¿沉积和淀粉样斑块形成，但不发生nft。AD和Tg小鼠大脑差异的一种可能解释是存在根本不同的A¿菌株。了解这一问题对于开发新的A¿导向疗法非常重要，因为可以想象，对小鼠脑源性A¿构象有活性的化合物对人类脑源性A¿菌株无效，这是一个在朊病毒疾病中反复遇到的问题。因此，本提案的目标是开发描述和分类大脑中可能的A¿构象范围的方法，以及分析不同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期）和三年的独立研究（R00期）中，这些实验将确定Tg小鼠和AD患者的大脑中是否存在不同的A¿肽构象。这些研究是开发新的细胞和动物模型的必要的第一步，这些模型更准确地概括了阿尔茨海默病的重要生物学事件，并可能为开发和测试潜在的阿尔茨海默病治疗方法提供更多信息。

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. PUBLIC HEALTH RELEVANCE: With an aging population and the absence of an effective treatment, the social and economic costs of Alzheimer's disease will skyrocket in the coming years. One potential explanation for the lack of therapeutic success is that the genetically modified mice used to study this disease are poor models of the human condition. This proposal will test whether the A¿ peptide, the pathological entity that causes death of brain cells during Alzheimer's disease, is fundamentally different in the brains of mice and Alzheimer's disease patients, which could potentially lead to more informative tools for developing therapeutics.