Communicating Intestinal Inflammation to the Brain in Alzheimer's Disease

阿尔茨海默氏病中肠道炎症与大脑的沟通

• 批准号: 10472821
• 负责人: Colin K Combs
• 金额: $ 19.12万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472821
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Antibodies; Antibody Therapy; Attenuated; Brain; Chronic; Clinical; Colitis; Crohn' s disease; Data; Disease; Disease Progression; Elderly; Functional disorder; Gastrointestinal tract structure; Gliosis; Immunomodulators; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Diseases; Intestines; Link; Memory impairment; Mus; Neurodegenerative Disorders; Peyer' s Patches; Prevalence; Risk; Role; Severities; Synapses; T-Lymphocyte; Testing; Therapeutic; Transgenic Mice; Tumor Necrosis Factor-Beta; Ulcerative Colitis; base; blood-brain barrier crossing; blood-brain barrier permeabilization; brain tract; combat; cytokine; genetic approach; gut inflammation; gut-brain axis; intestinal epithelium; lymph nodes; mouse model; novel therapeutic intervention; null mutation; prevent

Project Summary The brain communicates with the gastrointestinal tract via the well-established gut-brain axis. Due to an increase in the permeability of blood brain barrier and intestinal epithelial barrier during aging, the brain likely becomes more susceptible to inflammation initiated in the gut. Both chronic inflammatory bowel disease (IBD including ulcerative colitis and Crohn’s disease) and Alzheimer’s disorder (AD) increase in prevalence among the elderly. However, the role of this intestinal inflammation on AD progression remains unclear. We observed a significant increase in intestinal inflammation and dysfunction during disease in a mouse model of AD. Based upon this data we hypothesize that AD includes intestinal dysfunction as a largely unrecognized component of disease. Moreover, we expect that chronic conditions such as IBD may potentiate progression of AD through inflammatory changes propagated from the intestines to the brain. We will elaborate the link between the intestines and the brain in AD using a transgenic mouse model of AD, AppNL-G-F mice. Our hypothesis will be tested by completing three aims. Aim one will use clinically available intestine-selective T cell inhibitory antibodies to attenuate basal AD intestinal inflammation and colitis-induced exacerbation in AppNL-G-F mice and confirm that intestinal dysfunction contributes to memory deficits in these mice. Aim two will assess the efficacy of the gut-selective inhibitory antibody therapy to decrease brain Aβ levels, gliosis, synaptic loss, and cytokine levels. The final aim will cross the AppNL-G-F mice to Ltatm1Dch mice that carry a null mutation in lymphotoxin α resulting in absence of Peyer’s patches and lymph nodes. This genetic approach will provide additional confirmation that intestinal inflammatory changes in the AppNL-G-F mice are required for the memory dysfunction and brain related changes. Completion of the study will verify a critical role of gut inflammation in disease progression and validate a clinically available therapeutic option, anti-α4β7 antibodies, as treatments targeting the gut-brain axis. This suggests that select immunomodulatory agents can be repositioned to combat the inflammatory component of AD without the need for crossing the blood brain barrier.

项目摘要 大脑通过已建立的肠道-脑轴与胃肠道进行交流。由于 衰老过程中血脑屏障和肠上皮屏障通透性增加，大脑可能 变得更容易受到肠道发炎的影响。慢性炎症性肠病(IBD) 包括溃疡性结肠炎和克罗恩病)和阿尔茨海默病(AD)的患病率在 老年人。然而，这种肠道炎症在AD进展中的作用尚不清楚。我们观察到 在阿尔茨海默病小鼠模型中，疾病期间肠道炎症和功能障碍显著增加。基座 根据这一数据，我们假设AD包括肠道功能障碍，作为一个很大程度上未被认识到的组成部分 疾病。此外，我们预计像IBD这样的慢性疾病可能通过以下途径加强AD的进展 炎性变化从肠道传播到大脑。我们将详细说明 用转基因AD小鼠模型AppNL-G-F小鼠进行AD肠道和脑组织的研究。我们的假设是 通过完成三个目标进行测试。目的一是使用临床可用的肠道选择性T细胞抑制 减轻基础AD肠炎和结肠炎诱导的AppNL-G-F小鼠恶化的抗体和 确认肠道功能障碍是导致这些小鼠记忆缺陷的原因。目标二将评估其疗效 肠道选择性抑制性抗体治疗降低脑Aβ水平、胶质细胞增生症、突触丢失和细胞因子 级别。最终目标是将AppNl-G-F小鼠与携带淋巴毒素α零突变的Ltatm1Dch小鼠杂交 导致皮耶氏斑和淋巴结节缺失。这种遗传方法将提供额外的 确认AppNL-G-F小鼠的肠道炎症改变是记忆功能障碍所必需的 以及与大脑相关的变化。这项研究的完成将证实肠道炎症在疾病中的关键作用 进展和验证临床可用的治疗选择，抗α4β7抗体作为靶向治疗 内脏-脑轴。这表明，选定的免疫调节剂可以重新定位，以对抗 阿尔茨海默病的炎症成分，不需要穿过血脑屏障。