Exploring the contribution of viral PP2A inhibition to tau pathology in Alzheimer's disease.

项目摘要 目前还没有针对阿尔茨海默病(AD)和我们的穷人的疾病修正疗法 对促进其发展的因素的了解是确定 对这种疾病采取有效的预防措施或治疗。这项建议旨在推进我们的 通过检验感染表达蛋白质抑制物的病毒的假设来理解AD的病因学 磷酸酶2A(PP2A)参与其发育过程。具体地说，我们将测试一个模型，其中感染 通过PP2A抑制病毒可能通过触发tau病理而促进AD的发生，tau病理随后从受感染的 以与AD进展一致的模式将细胞转移到邻近的细胞和大脑区域。这一假设得到了支持 根据在人类和动物模型中进行的研究得出的三条公认的证据，包括： 证据表明PP2A在AD和tau病理中的作用，tau病理传播的观察 以及多种人类病毒表达PP2A抑制蛋白是一种共同的策略 以利用其宿主细胞的生理学。在这项提案中，我们将使用一种新颖的、 最先进的方法(ViroCap)和激光捕获显微解剖来识别和测试相关性 病毒感染部位和tau组织病理学之间的关系。这项工作将促进我们对这些因素的理解 有助于AD的发展，具有潜在的临床应用，包括测试的开发 为了确定由于感染PP2A抑制病毒而导致AD风险增加的个人， 开发疫苗或抗病毒疗法，以防止因感染这些病毒而导致的AD风险增加 病毒，或开发药物干预措施，通过以下方式降低受感染个人的AD风险 提高PP2A活性。在这项提案中，我们还将创建一个tau病理播种的动物模型。 通过病毒PP2A抑制剂用于了解其潜在的作用机制和识别潜在的 与之抗争的治疗方法。

Project Summary There is currently no disease modifying treatment available for Alzheimer’s disease (AD) and our poor understanding of the factors that contribute to its development stands as a significant barrier to identifying effective preventative measures or treatments for this disease. This proposal seeks to advance our understanding of AD etiology by testing the hypothesis that infection with viruses that express inhibitors of protein phosphatase 2A (PP2A) can contribute to its development. Specifically, we will test a model wherein infection by PP2A inhibiting viruses could contribute to AD by triggering tau pathology that then propagates from infected cells to adjacent cells and brain regions in a pattern consistent with AD progression. This hypothesis is supported by three well-established lines of evidence from studies conducted in humans and animal models including: evidence demonstrating a role for PP2A in AD and tau pathology, the observation that tau pathology propagates to adjacent cells, and the fact that multiple human viruses express PP2A inhibiting proteins as a common strategy for coopting the physiology of their host cells. In this proposal, we will screen human brain tissue using a novel, state of the art method (ViroCap) and laser capture microdissection to identify and to test for associations between sites of viral infection and tau histopathology. This work will advance our understanding of the factors that contribute to the development of AD, with potential clinical applications including the development of tests to identify individuals at increased risk for AD as a result of infection with PP2A inhibiting viruses, the development of vaccines or antiviral therapies to prevent increased AD risk resulting from infection with these viruses, or the development of pharmacological interventions that reduce AD risk in infected individuals by increasing PP2A activity. In this proposal, we will also create an animal model of the seeding of tau pathology by viral PP2A inhibitors for use in understanding the mechanisms underlying their effects and identifying potential therapeutic approaches to combat them.