Alzheimer's Disease associated pathology induced by neurotropic viral infection

摘要 阿尔茨海默病的遗传风险因素可以预测患该病的可能性增加，但它 越来越明显的是，外部因素参与了神经退行性疾病的进展。 最近，两种疱疹病毒被认为与这种疾病有关，因为它们在病变组织中被发现。 阿尔茨海默氏症患者。人类单纯疱疹病毒1型(HSV-1)和人类疱疹病毒6a(HHV6a)分别是 嗜神经性疱疹病毒，建立神经系统的裂解性和终生潜伏性感染。多么 这些病毒病原体改变了神经退行性疾病的结果，但仍未确定其特征。阿尔茨海默氏症 疾病的特点是宿主蛋白的明显变化，包括Tau的错误折叠。使用一个新奇的人类 在IPSC衍生的3D皮质模型系统中，我们观察到编码Tau的mRNA的剪接变化。 此外，我们观察到依赖病毒感染的磷酸化Tau的积累增加，这是一种后 翻译修饰表明Tau的错误折叠。这些初步发现支持这一假设。 病毒感染直接影响宿主细胞微环境，导致阿尔茨海默病的变化 记号笔。这些研究的首要目标是确定影响 阿尔茨海默病进展的严重程度或频率。这项建议的目标是界定 嗜神经性疱疹病毒感染对阿尔茨海默病已知致病因素积累的生物学影响 生理相关模型系统内的疾病。我们的首要目标是识别和定义病毒依赖 参与神经退化的多个宿主蛋白内的变化。这将是第一次，直接联系 嗜神经性病毒感染与细胞内致病性神经退行性变之间具有临床相关性。这个 第二个目标是使用新的RNA标记协议来描述仅来自受感染细胞的转录组 3D有机化合物，并将利用单细胞测序来表征这些嗜神经病毒的趋向性。 第三个目标是利用3D有机化合物，这些有机化合物含有在发病时发现的已知遗传风险因素突变 并将确定疱疹病毒是否会放大神经退行性进展的开始。 成功完成将明确定义影响阿尔茨海默病的病毒因素，并将提供 对阿尔茨海默病以外的致病机制的洞察。

SUMMARY Genetic risk factors for Alzheimer's Disease can predict the increased likelihood of acquiring the disease yet it is becoming more evident that external factors are involved in the neurodegenerative disease progression. Recently two herpesviruses have been implicated in this disorder as they have been found in diseased tissues of Alzheimer's patients. Human herpes simplex virus 1 (HSV-1) and Human Herpesvirus 6a (HHV6a) are neurotropic herpesviruses that establish both lytic and lifelong latent infections of the nervous system. How these viral pathogens alter the outcome of neurodegenerative disease remains uncharacterized. Alzheimer's Disease is marked by distinct alterations of host proteins including the misfolding of Tau. Using a novel human iPSC-derived 3D cortical model system, we observed altered splicing of the mRNA that encodes Tau. Additionally, we observe a viral infection dependent increase in the accumulation of phospho-Tau, a post translational modification indicating the misfolding of Tau. These preliminary findings support the hypothesis that viral infections directly impact the host cell microenvironment resulting in changes in Alzheimer's Disease markers. The overarching goal of these studies is to identify infectious etiological agents that impact either the severity or frequency of Alzheimer's Disease progression. The objective of this proposal is to define the biological impact of neurotropic herpesvirus infections on accumulation of known drivers of Alzheimer's disease within a physiologically relevant model system. Our first aim will identify and define viral dependent changes within multiple host proteins involved in neurodegeneration. This will for the first time, a direct link between neurotropic virus infections and pathogenic neurodegenerations in cells of clinical relevance. The second aim will use novel RNA labeling protocols to profile the transcriptome from only infected cells within the 3D organoids and will utilize single cell sequencing to characterize the tropism of these neurotropic viruses. The third aim will utilize 3D organoids that harbor known genetic risk factor mutations found in the onset of Alzheimer's Disease and will determine if herpesviruses amplify the onset of neurodegenerative progression. Successful completion will clearly define the viral factors that influence Alzheimer's disease and will provide insight in pathogenic mechanisms that extend beyond Alzheimer's Disease.