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：
10653255
负责人：
Laren Becker
金额：
$ 36.24万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
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 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653255
关键词：
APP-PS1 Accounting Affect Age Age Months Aging Alzheimer&apos s Disease Alzheimer&apos s disease patient Amyloid beta-Protein Animal Disease Models Antibiotics Apoptosis Biology of Aging Brain Cells Characteristics Chronic Cognition Colon Constipation Data Dementia Deposition Development 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 Homeostasis Human IL18 gene ITGAX gene Immune Impaired cognition Impairment Individual Inflammasome Inflammation Inflammatory Interleukin-6 Intervention Lead Literature Macrophage Maps Measures Metagenomics Microglia Mus Neurodegenerative Disorders Neuroimmune Neuroimmune system Neurons PTPRC gene Pathogenesis Pathway interactions Peripheral Nervous System Phenotype Plasma Play Population Prevention Prevention strategy Probability Process Reporting Research Research Personnel Role Science Senile Plaques Signal Transduction Small Intestines Testing Time Tissues Transgenic Mice United States Wild Type Mouse abeta accumulation age group age related brain tissue cell motility cognitive change cognitive function cytokine experimental study fecal transplantation gain of function gastrointestinal genetic signature gut microbiota gut-brain axis host microbiota immune cell infiltrate loss of function microbial microbiota motility disorder mouse model multidisciplinary neuroinflammation neuron loss novel probiotic supplementation spatiotemporal therapeutic target transmission process

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，包括便秘和大便失禁，常见于患有以下疾病的患者：阿尔茨海默病 (AD) 是痴呆症的最常见原因，这些疾病也很常见。在老年人中，这增加了一种可能性，即共同的过程可能是导致两者肠道紊乱的原因 AD 和衰老。在患有 AD 的人类和 AD 动物模型中，β 淀粉样蛋白 (Aβ) 斑块是该疾病的标志之一，已在肠神经系统 (ENS) 中检测到，肠神经系统是周围神经系统的一个自主分支跨越胃肠道并调节肠道蠕动的系统 Aβ 肠道积聚似乎会导致 ENS。神经炎症和肠道收缩力受损，但目前的文献排除了是否有明确的结论。鉴于神经退行性疾病的新报告不断出现，AD 如何影响肠道变得越来越重要拟议的多学科研究将整合这些疾病。 AD 科学与衰老的基本生物学相结合我们发现与年龄相关的肌层变化。巨噬细胞 (MM) 是 ENS 中组织驻留的巨噬细胞群，可驱动老年 ENS 炎症，这与胃肠道运动破坏和认知受损有关。这种 MM 改变取决于。微生物群中的因素并反映了小胶质细胞（主要的巨噬细胞）中发现的 AD 疾病状态根据这些发现，我们认为 AD 引起的 MM 变化与这些变化类似。见于老年受试者，导致 ENS 神经炎症、胃肠道运动改变和受损该假设将通过三个目标进行检验。首先，研究人员将评估 AD 是否会导致 ENS。以 MM 老年疾病状态 (GDS) 为特征的神经免疫变化。他们将评估是否存在这种变化。 MM 的改变导致老年 ENS 神经炎症，伴有免疫细胞浸润和促其次，研究人员将评估炎症细胞因子和肠神经元损失是否受到破坏。最后，通过对微生物群的实验操作，肠道蠕动先于认知受损。研究人员将探索宿主-微生物群相互作用在 AD 相关胃肠道疾病中的作用及其影响具体来说，研究人员将检查 AD 疾病是否进展以及如何进展。受到慢性抗生素、年轻或年老小鼠粪便的粪便微生物群移植或益生菌的影响补充阿克曼氏菌（Akkermansia mucinophila），这是一种在老年小鼠中减少的微生物群成分。成功完成拟议的研究将确定影响的关键病理生理学途径研究结果将为 AD 的新预防和干预策略提供信息。和与衰老相关的痴呆症。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Age-dependent Microglial Disease Phenotype Results in Functional Decline in Gut Macrophages.

年龄依赖性小胶质细胞疾病表型导致肠道巨噬细胞功能下降。

DOI：
发表时间：
2023
期刊：
影响因子：
0
作者：
Bishop, Estelle Spear;Namkoong, Hong;Aurelian, Laure;McCarthy, Madison;Nallagatla, Pratima;Zhou, Wenyu;Neshatian, Leila;Gurland, Brooke;Habtezion, Aida;Becker, Laren
通讯作者：
Becker, Laren