Contribution of the Virome to Alzheimer's pathogenesis

阿尔茨海默病(AD)是一种广泛存在的原因不明的老年性痴呆，其特征是 β淀粉样蛋白(神经炎性斑块)和微管相关tau的神经元丢失、萎缩和聚集 大脑中的蛋白质(神经原纤维缠结)。我们知识上的主要差距是什么触发了AD 发病机制。而这些蛋白的沉积被认为在糖尿病的发病机制中起着重要作用。 AD，这些聚集体的存在不足以引起AD。无论是人类还是实验动物 模型可以显示这两种神经病变中的一种或两种，而不会造成认知障碍。因此，在那里 一直在加紧努力识别其他危险因素，包括感染性病原体，以及蛋白质 聚集性可以完全解释这种多因素疾病的病因。特别是，有证据表明， 被病毒病原体感染，如疱疹病毒科病毒家族成员，可能是 开发AD。然而，像蛋白质聚集体一样，这些病毒也在相当数量的健康人群中发现 阿尔茨海默病患者的大脑中并没有持续的富集物。足够的力量和不偏不倚 需要对AD患者和精心挑选的对照受试者进行病毒遗传物质检测的研究 将病毒感染确定为真正的风险因素。此外，还进行了机械实验，考察了 在AD的发病机制中，这些药物是必要的，以便调和感染病因和更多 已确定的风险因素，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靶标浓缩深度测序 平台，ViroFind，用于识别临床组织样本中所有已知感染人类的病毒，包括POST 死亡大脑--整个病毒。我们的初步数据表明，腺相关病毒(AAV)是富集性的 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检测AD患者大脑中的完整病毒。我们的中心假设是已知的病毒、病毒 变异体或未知病毒能够到达中枢神经系统，并通过隐藏在神经元中而保持潜伏，从而 逃避免疫系统的检测。衰老过程中反复的重新激活会触发免疫和 产生Aβ的炎症反应，多年来导致某些基因携带者出现阿尔茨海默病 性情。理由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大脑中存在的所有病毒株，以及它们的细胞定位和它们是否 是潜伏的或复制的。为了验证这一假设，我们将执行以下具体目标： 目的1.确定病毒感染是否与成人神经发生的丧失有关 以及这些因素是否与AD的发生发展有关。

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.