Gut-Brain Axis in Alzheimer's Disease

项目摘要/摘要 本附录的父母R01正在研究帕金森氏病(PD)病理在外围的作用， 尤其是在肠道神经系统(ENS)。这些研究的理论基础是这样一个事实，即周围病理学(在 聚集的α-突触核蛋白(α-SYN)的形式被假设与胃肠(GI)功能障碍有关，如 也是最终导致大脑神经退化的病理来源。我们的初步调查结果是 证实ENSα-SYN病理确实导致胃肠道症状；然而，我们无法找到直接的证据 将病理转移到大脑(即通过“类病毒”转移)。然而，我们现在正在调查ENS是否 病理可以“旁分泌”的方式折磨大脑；例如，通过起源于 恩斯。在本补充材料中，我们提出，同样的前提也适用于与AD相关的外周病变(例如： Tau，淀粉样前体蛋白(APP))。为此，我们的中心假设认为，肠道AD病理的诱导 将导致全身性炎症，加剧AD神经变性啮齿动物模型的神经毒性。 有趣的是，对阿尔茨海默病相关病理的研究非常少见。这样做的原因很可能是 这源于这样一个事实，即胃肠道功能障碍并不是AD的前驱症状。然而，这并不是 有必要在AD中没有ENS病理。事实上，在人类AD中已经报道了一种β免疫反应斑块 患者，在转基因动物中发现了ENS病理。我们认为，任何这样的外周病变都会导致 全身性炎症，一种可使中枢神经元易于变性或使其变得敏感的疾病。发炎， 曾经被认为是神经变性的结果，现在越来越多地被认为是有致病作用的 阿尔茨海默病的神经退行性变。然而，我们仍然不知道到底是什么触发了神经炎症，而且还没有 了解炎症和神经退行性变之间的时间关系。在这里，我们将利用一本小说 为亲本R01开发的基因治疗方法，通过该方法，我们将在 脑神经的神经元。这种方法的一个关键方面是转基因表达在空间上限制在肠道内。 神经元和时间控制。这将使我们能够专门研究ENS病理学在疾病中的作用，而不是 在转基因动物中或在AAV系统传播后发现的普遍表达的混乱。在… 同时，我们还将利用AAV在中枢神经系统过度表达疾病相关蛋白。通过这种方法，我们预计 发现1)全身炎症标志物的增加，2)神经炎症指数的增加，以及3) 中枢神经元对突变型tau或app等疾病蛋白的易感性增加。如果这些结果中的任何一个是 被证明是真的，它将证明PNS的变化可以促进中枢神经系统疾病，为一种新的 AD研究领域。此外，如果我们能证明非细胞自主因素起作用，甚至触发， 神经退行性变，未来的一个重要焦点将是更好地了解分子中 神经细胞丢失的过程表明神经炎症起到了促进作用。

Project Summary/Abstract The parent R01 of this supplement is investigating the role of Parkinson’s disease (PD) pathology in the periphery, specifically in the enteric nervous system (ENS). The rationale for these studies is the fact that peripheral pathology (in the form of aggregated alpha-synuclein (α-syn)) is hypothesized to be linked both to gastrointestinal (GI) dysfunction as well as being the source of pathology that eventually leads to neurodegeneration in the brain. Our initial findings have confirmed that ENS α-syn pathology does cause GI symptoms; however, we were unable to find evidence of a direct transfer of pathology to the brain (i.e. via “prion-like” transfer). However, we are now investigating whether the ENS pathology can afflict the brain in a “paracrine” fashion; for instance, via enhanced inflammation originating from the ENS. In this supplement we propose that the same premise holds true for AD-related pathologies of the periphery (e.g. tau, amyloid precursor protein(APP)). To that end, our central hypothesis states that induction of enteric AD pathology will result in systemic inflammation that exacerbates neurotoxicity in rodent models of AD neurodegeneration. Interestingly, investigations into AD-related pathologies of the ENS are extremely rare. The reason for this is likely stemming from the fact that GI dysfunction is not a reported prodromal symptom in AD. This does, however, not necessitate the absence of ENS pathology in AD. In fact, Aβ-immunoreactive plaques have been reported in human AD patients, and ENS pathology is found in transgenic animals. We propose that any such peripheral pathology will induce systemic inflammation, a condition which can predispose or sensitize central neurons to degeneration. Inflammation, once thought to be a consequence of neurodegeneration, is becoming increasingly thought of as having a causative role in AD neurodegeneration. However, we still do not understand what exactly triggers neuroinflammation, and have yet to understand the temporal relationship between inflammation and neurodegeneration. Herein we will utilize a novel gene therapy method developed for the parent R01 whereby we will overexpress AD-related proteins specifically in neurons of the ENS. A crucial aspect of this approach is that transgene expression is spatially restricted to enteric neurons and temporally controlled. This will allow us to specifically study the role of ENS pathology in disease, without the confound of ubiquitous expression that can be found in transgenic animals, or following systemic delivery of AAV. At the same time, we will also utilize AAV to overexpress disease related proteins in the CNS. With this approach we expect to find 1) An increase in markers of systemic inflammation, 2) An increase in indices of neuroinflammation, and 3) Increased susceptibility to disease proteins such as mutant tau or APP in central neurons. If any of these outcomes are proven true, it will demonstrate that changes in the PNS can contribute to CNS disease, laying the foundation for a novel area of AD research. Moreover, if we can demonstrate that non-cell autonomous factors contribute, or even trigger, neurodegeneration, a significant focus moving forward will be to better understand exactly where in the molecular process of neuronal loss that neuroinflammation plays a contributory role.