Altered ENS Neuroimmune Interactions Disrupt Gastrointestinal Motility in Alzheimers Disease

ENS 神经免疫相互作用的改变会破坏阿尔茨海默病的胃肠动力

基本信息

批准号：
10488581
负责人：
Laren Becker
金额：
$ 1.11万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10488581
关键词：
APP-PS1 Accounting Affect Age-Months Aging Alzheimer&apos s Disease Amyloid beta-Protein Animal Disease Models Antibiotics Apoptosis Biology of Aging Brain Cells Characteristics Chronic Cognition Colon Constipation Cytokine Activation Data Dementia Deposition Disease Disease Progression Disease associated microglia Elderly Enteral Enteric Nervous System Euthanasia Fecal Incontinence Feces Functional disorder Gastric Emptying Gastrointestinal Diseases Gastrointestinal Motility Gastrointestinal tract structure Human ITGAX gene Immune Impaired cognition Impairment Individual Inflammasome Inflammation Inflammatory Interleukin-18 Interleukin-6 Lead Literature Measures Metagenomics Microglia Mus Neurodegenerative Disorders Neuroimmune Neuroimmune system Neurons PTPRC gene Pathogenesis Pathway interactions Patients Peripheral Nervous System Phenotype Plasma Play Population Process Reporting Research Research Personnel Role Science Senile Plaques Signal Transduction Small Intestines Testing Time Tissues Transgenic Mice Tumor-infiltrating immune cells abeta accumulation age group age related brain tissue cell motility cognitive change cognitive development cognitive function cytokine experimental study fecal transplantation gain of function gastrointestinal genetic signature gut microbiota gut-brain axis host microbiota macrophage microbial microbiota mouse model multidisciplinary neuroinflammation neuron loss novel preventive intervention probiotic supplementation spatiotemporal therapeutic target

项目摘要

Abstract Gastrointestinal (GI) disorders including constipation and fecal incontinence are commonly found in patients with Alzheimer’s disease (AD), the most common cause of dementia. These same disorders are also frequently encountered in the elderly, raising the possibility that a common process may underlie gut disturbances for both AD and aging. In humans with AD and AD animal models, amyloid-β (Aβ) plaques, one of the disease hallmarks, have been detected in the enteric nervous system (ENS), an autonomous branch of the peripheral nervous system that spans the GI tract and regulates gut motility. Aβ gut accumulation appears to cause ENS neuroinflammation and impaired gut contractility but current literature precludes definitive conclusion. Whether and how AD involves the gut is of increasing importance given emerging reports that neurodegenerative disorders are transmitted from the gut to the brain. The proposed multidisciplinary study will integrate the science of AD with the basic biology of aging. We found that age-related changes to muscularis macrophages (MMs), a population of tissue-resident macrophages in the ENS, drive geriatric ENS inflammation, which is associated with disruption of GI motility and impaired cognition. This MM alteration is dependent on factors in the microbiota and mirrors an AD diseased state found in microglia, the predominant macrophage population of the brain. Following on these findings, we posit that AD causes MM changes similar to those seen in geriatric subjects that result in ENS neuroinflammation, altered GI motility and impaired cognition, and depend on host-microbiota interactions. This hypothesis will be tested with three aims performed in the APP/PS1 AD mouse model. First, the investigators will evaluate whether AD causes ENS neuroimmune changes characterized by a MM geriatric disease state (GDS). They will assess whether alterations in MMs lead to geriatric ENS neuroinflammation with infiltration of immune cells and elevated pro- inflammatory cytokines, and enteric neuronal loss. Second, the investigators will assess whether disruption in gut motility precedes impaired cognition. Finally, using experimental manipulation of the microbiota, the investigators will explore the role of host-microbiota interactions in AD-associated GI disease and their relationship to cognition. Specifically, the investigators will examine whether and how AD disease progression is affected by chronic antibiotics, fecal microbiota transplantation of stool from young or old mice, or probiotic supplementation with Akkermansia mucinophila, a microbiota component reduced in old mice. Successful completion of the proposed studies will identify critical pathophysiological pathways that affect the gut and precede cognitive decline. The results will inform novel prevention and intervention strategies for AD and aging-associated dementia.

抽象的胃肠道（GI）疾病在内阿尔茨海默氏病（AD），是痴呆症的最常见原因。这些相同的疾病也经常在古老的情况下遇到，提出了一个共同过程可能是肠道干扰的可能性广告和老化。在具有AD和AD动物模型的人类中，淀粉样蛋白β（Aβ）斑块（疾病标志之一）在肠神经系统（ENS）中已检测到，周围神经的自主分支跨GI区并调节肠道运动的系统。 Aβ肠道积累似乎会导致ENS 神经炎症和肠道收缩性受损，但目前的文献排除了明确的结论。无论鉴于神经退行性的新闻报道，AD涉及肠道的重要性越来越重要疾病从肠道传播到大脑。拟议的多学科研究将整合广告科学具有衰老的基本生物学。我们发现与年龄相关的肌肉变化巨噬细胞（MMS），ENS中的组织居民巨噬细胞，驱动老年注射，这与胃肠道运动的破坏和认知受损有关。此MM改变取决于微生物群中的因素，反映了小胶质细胞中发现的AD病态状态，这是主要的巨噬细胞大脑人群。按照这些发现，我们肯定AD会导致MM变化类似在导致ENS神经炎症，改变GI运动和受损的老年学科中可见认知，并依赖于宿主 - 微生物群的相互作用。该假设将以三个目标进行检验在应用程序/PS1 AD鼠标模型中执行。首先，调查人员将评估AD是否导致ENS 具有MM老年疾病状态（GDS）为特征的神经免疫变化。他们将评估是否 MMS的改变导致老年ENS神经炎症，免疫细胞浸润，并升高炎症细胞因子，进入神经元丧失。其次，调查人员将评估中断肠道运动先于认知受损。最后，使用微生物群的实验操纵，研究人员将探讨宿主 - 微生物群相互作用在与广告相关的胃肠病及其中的作用与认知的关系。具体而言，研究人员将检查AD疾病的进展以及如何发展受慢性抗生素的影响，年轻或老鼠的粪便菌群移植或益生菌补充Akkermansia粘蛋白粒细胞，旧小鼠中降低的微生物群。成功完成拟议的研究将确定影响影响的关键病理生理途径肠道和认知能力下降。结果将为AD的新型预防和干预策略提供信息和衰老相关的痴呆症。