Project 3

摘要(项目III) 在过去的十年里，越来越清楚的是，阿尔茨海默病(AD)是一种病理上的 经过几十年演变而来的复杂疾病。虽然阿尔茨海默病最常见的病理是共存 在淀粉样斑块和神经原纤维缠结中，约40%的AD病例还表现为α-突触核蛋白(AS)病理。 在AD患者中，TDP-43阳性包涵体也很常见。以遗传性为主的AD (FAD)，已经清楚地表明，A？的沉积发生在认知症状和 Tau病理的出现。尽管事件的顺序在散发性AD中可能不那么明显，但 人们认为AS和tau病理在FAD的疾病演变过程中是次要事件。一个 越来越多的文献表明，细胞内AS和tau病理的演变可能涉及一种 错误折叠的蛋白质构象沿解剖路径或在细胞间的Pron样扩散 离散的解剖结构。在这项应用的初步研究中，我们开发了一些模型，在这些模型中 我们可以通过外源接种AS来诱导AS和内源性tau病理。在目标1中，我们建议使用 转基因和播种的结合，以开发更真实地概括各种 阿尔茨海默病的病理改变。这些模型的一个重要特征是，通过播种，我们能够建立 起源，然后跟踪病理传播到邻近结构或解剖连接的结构。 如果错误折叠的蛋白质在细胞之间移动，就像我们的数据和来自其他实验室的数据所表明的那样，如果 这样的蛋白质被暴露在细胞间隙很长一段时间内，然后抗体定向 抗这些蛋白可能能够结合并抑制进一步的扩散。模型系统的开发 模拟人类病理的传播或传播，为测试新的免疫疗法提供了机会 为将这种疗法移植到人类身上提供概念证据。在目标2中，我们建议使用唯一的 这些可诱导模型在确定抗体潜在效力的概念验证研究中的特点 治疗。鉴于相当大比例的AD病例具有混合病理，并且这些病理 与神经退行性变独立相关，我们建议，为了获得最佳的临床益处， 可能需要开发针对多种类型的蛋白质包涵体病理的治疗方法。 因此，在这个项目中，我们将开发和测试针对A、AS和可能还有tau的免疫疗法。 总的来说，这些研究致力于AD中两个主要的未得到满足的需求，即生成更多 忠实再现人类疾病和疾病修饰疗法的发展。

SUMMARY (Project III) Over the past decade, it has become increasingly clear that Alzheimer's disease (AD) is a pathologically complex disorder that evolves over decades. Although the most common pathology of AD is the co-existence of amyloid plaques and neurofibrillary tangles, about 40% of AD cases also show a-synuclein (aS) pathology. It is also common to observe TDP-43 positive inclusions in AD cases. In dominantly inherited forms of AD (fAD), it has become clear that the deposition of A¿ occurs well before the onset of cognitive symptoms and the appearance of tau pathology. Although the order of events may be less obvious in sporadic AD, the perception is that aS and tau pathologies occur as secondary events in the evolution of disease for fAD. A growing body of literature suggests that the evolution of intracellular aS and tau pathology may involve a prion-like spreading of a misfolded protein conformation along anatomical pathways or between cells in discrete anatomical structures. In studies preliminary to this application, we have developed models in which we can induce aS and endogenous tau pathology by exogenous seeding with aS. In Aim 1, we propose to use a combination of transgenesis and seeding to develop models that more faithfully recapitulate the various pathologies of AD. An important feature of these models is that, by seeding, we are able to establish point of origin and then track the spread of pathology to adjacent structures or anatomically connected structures. If misfolded proteins are moving between cells, as our data and data from other laboratories suggest, and if such proteins are exposed to the intercellular space for a significant interval of time, then antibodies directed against these proteins may be able to bind and inhibit further spread. The development of model systems that mimic the spread, or transmission, of human pathology offers an opportunity to test novel immune therapies to provide proof of concept for moving such therapies to humans. In Aim 2, we propose to use the unique features of these inducible models in proof of concept studies to determine the potential efficacy of antibody therapies. Given that a substantial proportion of AD cases have mixed pathologies, and that these pathologies are independently associated with neurodegeneration, we propose that to achieve optimal clinical benefit it is likely that therapies need to be developed that can target more than one type of protein inclusion pathology. Thus, in this project, we will develop and test immunotherapeutics targeting A¿, aS, and possibly tau. Collectively, these studies work towards two major unmet needs in AD, the generation of models that more faithfully reproduce human disease and development of disease modifying therapies.