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.

阿尔茨海默病（AD）是一种广泛存在的病因不明的年龄相关性痴呆，其特征在于 神经元丢失、萎缩和β淀粉样蛋白（神经炎斑）和微管相关tau蛋白聚集 蛋白质（神经元缠结）。我们知识的主要差距是什么触发了AD 发病机制虽然这些蛋白质的沉积被认为在肿瘤的发病机制中起重要作用， AD，这些聚集体的存在不足以引起AD。人类和实验动物 模型可以表现出这些神经病理学变化中的一种或两种，而没有认知障碍。因此 一直在加大努力，以确定其他风险因素，包括传染性病原体， 聚集可以充分解释这种多因素疾病的病因。特别是，有证据表明， 病毒病原体如疱疹病毒科病毒成员的感染可能是 发展AD。然而，像蛋白质聚集体一样，这些病毒也存在于大量健康的人中。 个体中，并且在AD患者的脑中并不一致地富集。动力强劲，不偏不倚 需要在AD患者和精心选择的对照受试者中进行病毒遗传物质检测的研究， 确定病毒感染是真正的危险因素。此外，机械实验调查的作用， 需要这些在AD发病机制中的药物，以使感染性病因学与更多的 确定的风险因素，如衰老和病理性蛋白质聚集。 作为母公司DP1赠款的一部分，我们开发了一种无偏见的目标富集深度测序方法， ViroFind平台，用于鉴定临床组织样本中已知感染人类的所有病毒，包括感染后 尸体的大脑整个病毒库我们的初步数据表明，腺相关病毒（AAV）富集 在AD患者的大脑皮层中。 我们的长期目标是破译AD的发病机制。我们的总体目标是描述 使用ViroFind在AD患者的大脑中检测整个病毒组。我们的核心假设是已知的病毒， 变异体，或者说未知的病毒，能够到达中枢神经系统，并通过隐藏在神经元中保持潜伏状态， 逃避免疫系统的检测衰老过程中的反复激活会触发免疫， 炎症反应与Aβ的产生，这导致多年来在某些个体中的AD遗传 易感性我们的理据是，这些拟议的试验研究将使我们能够制定一个初步的 了解AD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 是潜伏的或复制的。为了验证这个假设，我们将执行以下特定目标： 目标1。确定病毒感染是否与成人神经发生的丧失有关， 海马以及这些因素是否与AD的发展有关。