Contribution of the Virome to Alzheimer's pathogenesis

病毒组对阿尔茨海默病发病机制的贡献

• 批准号: 10287010
• 负责人: Igor J Koralnik
• 金额: $ 32.74万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-14 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287010
• 关键词: Abeta synthesis; Ablation; Adult; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Atrophic; Attenuated; Autopsy; Brain; Cerebral cortex; Clinical; Data; Dementia; Dependovirus; Deposition; Detection; Development; Diagnostic; Disease; Etiology; Exhibits; Experimental Animal Model; Family; Genetic Materials; Genetic Predisposition to Disease; Goals; Grant; Herpes Simplex Infections; Herpesviridae; Herpesvirus 1; Hippocampus (Brain); Human; Human Herpesvirus 6; Immune; Immune system; Impaired cognition; In Situ Hybridization; Individual; Infection; Infectious Agent; Inflammatory; Knowledge; MAPT gene; Mission; Mus; National Institute of Drug Abuse; Neurofibrillary Tangles; Neurons; Parents; Pathogenesis; Pathologic; Patients; Pilot Projects; Play; Process; Proteins; Public Health; Reaction; Recombinant adeno-associated virus (rAAV); Recurrence; Reporting; Research; Risk Factors; Role; Senile Plaques; Severities; Staging; Testing; Therapeutic Intervention; Tissue Sample; Variant; Viral; Viral Genome; Virus; Virus Diseases; Work; abeta accumulation; adult neurogenesis; age related; aged; burden of illness; deep sequencing; experimental study; human disease; improved; member; neurogenesis; neuron loss; pathogenic virus; protein aggregation; sequencing platform; tau Proteins; virome; virus genetics

Alzheimer’s disease (AD) is a widespread age-related dementia of unknown etiology characterized by neuronal loss, atrophy, and aggregation of beta amyloid (neuritic plaques) and microtubule associated tau proteins (neurofibrillary tangles) in the brain. The major gap in our knowledge is what triggers AD pathogenesis. While deposition of these proteins are thought to play an important role in the pathogenesis of AD, the presence of these aggregates is not sufficient to cause AD. Both humans and experimental animal models can exhibit one or both of these neuropathological changes without cognitive impairment. Thus, there has been increasing effort to identify other risk factors, including infectious agents, that together with protein aggregation could fully explain the etiology of this multifactorial disease. In particular, there is evidence that infection by viral pathogens such as members of the Herpesviridae family of viruses could be risk factors for developing AD. However, like protein aggregates, these viruses are also found in a significant number of healthy individuals and are not consistently enriched in the brains of AD patients. Adequately powered and unbiased studies testing for viral genetic material in AD patients and carefully selected control subjects are needed to establish viral infection as a genuine risk factor. In addition, mechanistic experiments investigating the role of these agents in the pathogenesis of AD are needed in order to reconcile infectious etiologies with more established risk factors such as aging and pathological protein aggregation. As part of the parent DP1 grant, we have developed an unbiased target-enrichment deep-sequencing platform, ViroFind, for identifying all viruses known to infect humans in clinical tissue samples, including post mortem brains- the entire Virome. Our preliminary data indicate that adeno-associated virus (AAV) is enriched in the cerebral cortex of AD patients. Our long term goals are to decipher the pathogenesis of AD. Our overall objectives are to characterize the entire virome in the brain of AD patients using ViroFind. Our central hypothesis is that known viruses, viruses variants, or yet unknown viruses, are able to reach the CNS and remain latent by hiding into neurons, thereby escaping detection from the immune system. Recurrent reactivations during aging triggers an immune and inflammatory reaction with production of Aβ, which leads over the years to AD in certain individuals with genetic predisposition. The rationale is that these proposed pilot studies will enable us to develop an initial understanding of all the viral strains present in AD brains, as well as their cellular localization and whether they are latent or replicating.To verify this hypothesis, we will carry out the following Specific Aim: Aim 1. Determine whether viral infection correlates with the loss of adult neurogenesis in the human hippocampus and whether these factors are associated with the development of AD.

阿尔茨海默氏病（AD）是一种与年龄相关的广泛的病因，其特征是 β-淀粉样蛋白（神经斑）和微管相关的TAU的神经元丧失，萎缩和聚集 大脑中的蛋白质（神经原纤维缠结）。我们所知的主要差距是触发广告 发病。尽管这些蛋白质的沉积被认为在 AD，这些聚集体的存在不足以引起AD。人类和实验动物 模型可以在没有认知障碍的情况下表现出一种或两种神经病理学变化。那，那里 越来越多的努力来识别其他风险因素，包括传染剂，这些因素与蛋白质一起 聚集可以完全解释这种多因素疾病的病因。特别是有证据表明 病毒病原体（例如病毒家族的成员）感染的风险因素可能是 开发广告。但是，像蛋白质骨料一样，这些病毒也在大量健康中发现 个体，并不始终富含AD患者的大脑。充分动力和公正 需要研究AD患者中病毒遗传物质的研究和精心选择的对照对象的研究 将病毒感染作为真正的危险因素。此外，调查了的机械实验 为了使感染性病因与更多 确定的危险因素，例如衰老和病理蛋白质聚集。 作为父级DP1赠款的一部分，我们开发了一个无偏见的目标深入的深入阶段 平台（Vierofind Mortem Brains-整个病毒蛋白。我们的初步数据表明腺相关病毒（AAV）富含 在AD患者的大脑皮层中。 我们的长期目标是破译AD的发病机理。我们的总体目标是表征 使用Virofind的AD患者大脑中的整个病毒蛋白。我们的中心假设是已知的病毒，病毒 变体或未知病毒能够通过隐藏神经元来到CNS并保持潜在 从免疫系统中逃脱检测。衰老期间的复发激活会触发免疫和 与Aβ产生的炎症反应，多年来导致某些遗传的人的AD 倾向。理由是这些拟议的试点研究将使我们能够开发一个初始的 了解广告大脑中存在的所有病毒株，以及它们的细胞定位以及它们是否是否 为了验证这一假设，我们将执行以下具体目标： 目标1。确定病毒感染是否与人类成年神经发生的丧失相关 海马以及这些因素是否与AD的发展有关。