权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of IgA-biome in intestinal dysbiosis and brain changes in Alzheimer's disease

IgA 生物组在阿尔茨海默病肠道菌群失调和大脑变化中的作用

基本信息

批准号：
10667011
负责人：
Suba Nookala
金额：
$ 21.15万
依托单位：
UNIVERSITY OF NORTH DAKOTA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667011
关键词：
16S ribosomal RNA sequencing APP-PS1 Address Age Alzheimer&apos s Disease Alzheimer&apos s disease model American Amyloid Amyloid beta-Protein Antibodies Appearance Attenuated Awareness Bacteria Behavior Behavioral Binding Biochemical Biological Markers Blood Brain Burkholderiaceae C57BL/6 Mouse Chemosensitization Clinical Crohn&apos s disease Data Deterioration Disease Disease Progression Disease model Enteral Environmental Risk Factor Epithelium Etiology Family Female Functional disorder Future Genetic Genotype Gliosis Health Histologic Immune Immune system Immunoglobulin A Immunologics Impairment Individual Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interdisciplinary Study Intestines Investigation Memory Memory impairment Meninges Monitor Mus Nerve Degeneration Oral Outcome Pathogenicity Pathologic Pattern Peripheral Permeability Phenotype Population Reporting Role Sampling Secretory Immunoglobulin A Sex Differences Signal Transduction Sorting Spleen Streptococcaceae System Testing Therapeutic Therapeutic Intervention Time Toxin Transgenic Mice Transgenic Organisms Transplantation Ulcerative Colitis United States Wild Type Mouse Work absorption age related neurodegeneration behavior change cognitive function cytokine diagnostic biomarker dysbiosis gut bacteria gut inflammation gut microbiota gut-brain axis immunoregulation innovation intestinal epithelium intestinal homeostasis male microbial mouse model neuropathology novel strategies pathogen pathogenic bacteria prevent receptor sex therapeutic target tool

项目摘要

Summary An estimated 6.2 million individuals have Alzheimer’s disease (AD) in the US, which is projected to nearly triple by 2050. Although genetic and several environmental factors help explain the etiology of AD, emerging reports recognize significant associations between altered diversity, abundance, and composition of the intestinal microbiota, intestinal dysfunction, loss of epithelial barrier integrity, and the progression of AD. However, it is difficult to distinguish associations from causal relationships. Nevertheless, it is apparent that the dysbiotic gut microbial community elicits inflammatory features extending beyond the enteric system and stimulates aberrant and pathological brain changes. Intestinal homeostasis relies on secreted IgA that coats pathogenic bacteria and blocks their contact with epithelial receptors to avert inflammatory responses. We will test the idea that IgA-coated bacteria (IgA-biome) in the dysbiotic intestine are pathogenic and responsible for the direct potentiation of AD. Our preliminary data using a transgenic AppNL-G-F mouse model of AD demonstrated a significant increase in the levels of IgA-coated fecal bacteria in female mice. Moreover, 16s rRNA sequencing of IgA sorted bacteria (IgA-seq) from 12-month-old female AppNL-G-F and C57BL/6 wild-type mice identified distinct differences in the microbial taxa coated by IgA. These data were concomitant with behavior changes seen only in the female AppNL-G-F mice suggesting a nexus between the IgA-biome, gut, and brain. We will fully characterize the longitudinal changes in the IgA-biome by IgA-seq in Aim one and determine whether distinct IgA coated bacteria correlate with changes in immune phenotype, memory, gliosis, and -amyloid accumulation. In Aim two, we will validate the role of IgA in the dysbiosed AD gut by oral gavage transfer of IgA-biome from old into young mice and assess sex and genotype-dependent changes in behavior, gliosis, - amyloid accumulation, and peripheral and intestinal immunomodulatory changes. Our work will provide a new understanding of the IgA-biome as a contributor to brain changes in AD and may be relevant to other neurodegenerative conditions. We will also identify the unique age and disease patterns of IgA-biome taxa that can be potential diagnostic biomarkers and therapeutic targets.

总结