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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：
10229661
负责人：
Laren Becker
金额：
$ 39.92万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229661
关键词：
APP-PS1 Accounting Affect Age-Months Aging Alzheimer&apos s Disease Amyloid beta-Protein Animal Disease Models Animals Antibiotics Apoptosis Biology of Aging Brain Cells Characteristics Chronic Cognition Cognitive Constipation Cytokine Activation Data Dementia Disease Disease Progression Elderly Enteral Enteric Nervous System Euthanasia Fecal Incontinence Feces Functional disorder 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 Preventive Intervention Process Publishing Reporting Research Research Personnel Role Science Senile Plaques Signal Transduction Small Intestines Testing Time Tissues Transgenic Mice Tumor-infiltrating immune cells abeta accumulation age related 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 probiotic supplementation response therapeutic target

项目摘要

Project Summary/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.

项目总结/文摘