Innovating high-resolution novel imaging approaches to elucidate mechanisms of prion-like spreading of neurodegenerative disease

项目摘要/摘要： 随着人口老龄化，阿尔茨海默病等神经退行性疾病的患病率正在增加。几乎没有任何一种疗法可以治疗这些疾病。尽管它们的临床表现不同，但一个统一的主题是错误折叠的蛋白质在患有这些疾病的患者的大脑中积累。在神经退行性疾病研究中，一个令人兴奋的新领域，特别是阿尔茨海默病，是神经退行性疾病蛋白质类病毒传播的新现象。海绵状脑病的基础是基于蛋白质的感染性病原体，这一点已被证实。在这些罕见的，尽管是毁灭性的疾病中，Pron蛋白从正常的可溶形式转变为聚集的自我模板感染形式。这一过程引发了不可阻挡的病理传播和整个大脑的或有神经退化。但是，这种疾病机制是否会延伸到帕金森氏病(PD)和阿尔茨海默病等更常见的神经退行性疾病？如果是这样的话，它代表着在理解疾病机制方面的游戏规则改变者，并为治疗开发开辟了许多新的途径。然而，任何对类病毒传播的治疗性或机械性研究都需要开发强大的新成像方法来跟踪类病毒传播的路径，并了解这些蛋白质聚集体在传播时如何改变大脑功能。我们需要了解为什么他们会选择一些路线，而不是其他路线，以及这是如何影响大脑功能的。为了应对这一挑战，我们组建了一个跨学科团队，由一名工程师和一名遗传学家组成。首先，我们将使用最先进的大脑清理技术来获得类普里子蛋白传播的高分辨率图像，当这些聚集体从一个神经元扩散到另一个神经元时，我们将监控它们，跟踪它们的路径，并找出它们为什么走一些路线而不是其他路线。然后，我们将利用先进的高分辨率光遗传功能磁共振成像(OfMRI)来揭示类病毒传播对大脑网络活动和类病毒传播活动的纵向影响。我们的实验将为包括阿尔茨海默病在内的神经退行性疾病的普恩病毒样传播提供基本的机制洞察。我们应用的工具和我们学到的教训很可能广泛适用于神经退行性疾病，包括阿尔茨海默病。

PROJECT SUMMARY/ABSTRACT: Neurodegenerative diseases, such as Alzheimer’s disease, are increasing in prevalence with our aging population. There are virtually no treatments to any of these disorders. Although disparate in their clinical presentation, a unifying theme is the accumulation of misfolded proteins in the brains of patients afflicted with these diseases. An exciting new area in neurodegenerative disease research generally, and Alzheimer’s disease specifically, is the emerging phenomenon of prion-like spreading of neurodegenerative disease proteins. Prions are well established as the protein-based infectious agent underlying the spongioform encephalopathies. In these rare, albeit devastating, diseases the prion protein converts from the normal soluble form to the aggregated self-templating infectious form. This process initiates an inexorable spread of pathology and contingent neurodegeneration throughout the brain. But could this disease mechanism extend to the more common neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease? If so, it represents a game changer in terms of understanding disease mechanisms and opens many new avenues for therapeutic development. However, any therapeutic or mechanistic investigation into prion-like spreading will require the development of powerful new imaging approaches to track the path of prion-like spread and understand how these protein aggregates alter the brain function as they spread. We will need to understand why they take some routes but not others and how this impacts brain function. To address this challenge, we have formed an interdisciplinary team, consisting of an engineer and a geneticist. First, we will use state of the art brain clearing technology to obtain high-resolution images of prion-like protein propagation monitor these aggregates as they spread from one neuron to the next, tracking their paths, and figuring out why they take some routes but not others. Then, we will utilize the advanced high-resolution optogenetic functional magnetic resonance imaging (ofMRI) to reveal the longitudinal effects of prion-like spreading on brain network activity and activity on prion-like spreading. Our experiments will provide fundamental mechanistic insight into prion-like spread of neurodegenerative disease including Alzheimer’s disease. The tools we apply and the lessons we learn will likely be broadly applicable to neurodegenerative diseases, including Alzheimer’s disease.