Gut-Brain Axis in Alzheimer's Disease

阿尔茨海默病的肠脑轴

• 批准号: 9717825
• 负责人: Fredric Manfredsson
• 金额: $ 34.95万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9717825
• 关键词: Acute; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Animals; Area; Astrocytes; Astrocytosis; Behavior assessment; Blood; Brain; CNS degeneration; Central Nervous System Diseases; Chronic; Clinical; Clinical Research; Colon; Data; Deposition; Descending colon; Disease; Disease Progression; Enteral; Enteric Nervous System; Event; Exhibits; Foundations; Functional disorder; Hippocampus (Brain); Human; Inflammation; Inflammatory; Injections; Intestines; Investigation; Knock-out; Lead; Link; London; Memory impairment; Methods; Microglia; Modeling; Molecular; Monitor; Mutation; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Operative Surgical Procedures; Outcome; Parents; Parkinson Disease; Participant; Pathogenicity; Pathologic; Pathology; Patients; Peripheral; Peripheral Nervous System; Phenotype; Physiological; Play; Population; Predisposition; Process; Production; Proteins; Reporting; Research; Rodent Model; Role; Source; Submucosa; Symptoms; T-Lymphocyte; Technology; Time; Transgenic Animals; Transgenic Mice; Viral; Volatile Fatty Acids; Work; alpha synuclein; brain cell; cell motility; central sensitization; experimental study; extracellular; gastrointestinal; gastrointestinal symptom; gene therapy; gut-brain axis; immunoreactivity; indexing; inflammatory marker; microbiota; mouse model; mutant; negative affect; neuroinflammation; neuron loss; neurotoxicity; new therapeutic target; novel; overexpression; paracrine; pathogen; prion-like; protein aggregation; protein expression; stem; tau Proteins; tau mutation; transgene expression

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.

项目总结/摘要 这种补充剂的母体R 01正在研究帕金森病（PD）病理在外周中的作用， 特别是肠神经系统（ENS）。这些研究的基本原理是外周病理学（在 聚集的α-突触核蛋白（α-syn）的形式）被假设与胃肠道（GI）功能障碍有关， 也是最终导致大脑神经退化的病理学根源。我们的初步发现 证实ENS α-syn病理学确实引起GI症状;然而，我们无法找到直接的证据， 病理转移到大脑（即通过“朊病毒样”转移）。然而，我们现在正在调查ENS是否 病理学可以以“旁分泌”方式折磨大脑;例如，通过源自大脑的炎症增强， 少尉在本补充中，我们提出同样的前提适用于AD相关的外周病变（例如， tau，淀粉样前体蛋白（APP））。为此，我们的中心假设指出，诱导肠道AD病理 将导致全身性炎症，加剧AD神经变性啮齿动物模型中的神经毒性。 有趣的是，对ENS的AD相关病理的研究非常罕见。原因很可能是 这是因为GI功能障碍不是AD的前驱症状。然而，这并不 需要在AD中不存在ENS病理。事实上，在人类AD中已有Aβ免疫反应斑块的报道 在转基因动物中发现了ENS病理学。我们认为任何这样的外周病变都会诱导 全身性炎症，一种可使中枢神经元易于变性或使其敏感的病症。炎症， 曾经被认为是神经退行性变的结果，现在越来越多地被认为具有致病作用， AD神经退行性变然而，我们仍然不知道到底是什么引发了神经炎症， 了解炎症和神经退化之间的时间关系。在这里，我们将利用一本小说 为亲本R 01开发的基因治疗方法，由此我们将特异性地过表达AD相关蛋白， 这种方法的一个关键方面是转基因表达在空间上局限于肠神经元。 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， 在转基因动物中或在AAV的全身递送后发现的普遍表达的混淆。在 同时，我们还将利用AAV在中枢神经系统中过表达疾病相关蛋白。通过这种方法，我们希望 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） 增加对疾病蛋白的易感性，如中枢神经元中的突变tau或APP。如果这些结果中的任何一个 证明是真的，它将证明PNS的变化可以导致CNS疾病，为一种新的 AD研究领域。此外，如果我们能够证明非细胞自主因素有助于，甚至触发， 神经退行性变，一个重要的焦点向前发展将是更好地了解在分子中的确切位置， 在神经元损失的过程中，神经炎症起着促进作用。