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.

项目概要 大脑通过完善的肠脑轴与胃肠道进行交流。由于一个 衰老过程中血脑屏障和肠上皮屏障的通透性增加，大脑可能 变得更容易受到肠道引发的炎症的影响。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）的患病率增加 老年人。然而，这种肠道炎症对 AD 进展的作用仍不清楚。我们观察到 在 AD 小鼠模型中，疾病期间肠道炎症和功能障碍显着增加。基于 根据这些数据，我们假设 AD 包括肠道功能障碍，这是一种很大程度上未被认识到的组成部分。 疾病。此外，我们预计 IBD 等慢性疾病可能会通过以下方式促进 AD 的进展： 炎症变化从肠道传播到大脑。我们将详细阐述两者之间的联系 使用 AD 转基因小鼠模型 AppNL-G-F 小鼠对 AD 中的肠道和大脑进行了研究。我们的假设是 通过完成三个目标进行测试。目标一是使用临床可用的肠道选择性 T 细胞抑制剂 减轻 AppNL-G-F 小鼠基础 AD 肠道炎症和结肠炎诱发的恶化的抗体 证实肠道功能障碍导致这些小鼠的记忆缺陷。目标二将评估功效 肠道选择性抑制性抗体疗法可降低大脑 Aβ 水平、神经胶质增生、突触损失和细胞因子 水平。最终目标是将 AppNL-G-F 小鼠与携带淋巴毒素 α 无效突变的 Ltatm1Dch 小鼠杂交 导致没有派尔氏淋巴结和淋巴结。这种遗传方法将提供额外的 证实 AppNL-G-F 小鼠肠道炎症变化是记忆功能障碍所必需的 和大脑相关的变化。该研究的完成将验证肠道炎症在疾病中的关键作用 进展并验证临床可用的治疗选择，抗 α4β7 抗体，作为靶向治疗 肠脑轴。这表明可以重新定位选定的免疫调节剂来对抗 AD 的炎症成分，无需穿过血脑屏障。