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 大脑通过良好的肠脑轴与胃肠道通信。由于一个 衰老过程中血液脑屏障和肠上皮屏障的渗透性增加，大脑可能 它变得更容易受到肠道炎症的影响。两种慢性炎症性肠病（IBD） 包括溃疡性结肠炎和克罗恩病）和阿尔茨海默氏症（AD）的疾病（AD）增加 较早的。但是，这种肠道炎症在AD进展中的作用尚不清楚。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的显着增加。基于 根据这些数据，我们假设AD包括肠道功能障碍，这是很大程度上未识别的组成部分 疾病。此外，我们期望诸如IBD之类的慢性条件可能会通过AD的潜在发展 炎症变化从肠道传播到大脑。我们将详细说明 使用AppNL-G-F小鼠的AD的转基因小鼠模型，肠和大脑在AD中的大脑。我们的假设将是 通过完成三个目标测试。 AIM将使用临床上可用的肠道选择性T细胞抑制 减轻AppNL-G-F小鼠中碱性肠道注射和结肠炎加重的抗体， 确认肠功能障碍有助于这些小鼠的记忆定义。目标两个将评估效率 肠道选择性抑制性抗体疗法，可降低脑Aβ水平，神经胶质症，突触损失和细胞因子 水平。最终目标将跨越AppNL-G-F小鼠到LTATM1DCH小鼠，该小鼠在淋巴毒素α中携带无效突变 导致没有佩耶的斑块和淋巴结。这种遗传方法将提供额外的 确认记忆功能障碍需要APPNL-G-F小鼠的肠炎症变化 和与大脑相关的变化。该研究的完成将验证肠道注射在疾病中的关键作用 进展并验证临床上可用的治疗选择抗α4β7抗体作为靶向的治疗 肠道轴。这表明可以重新定位某些免疫调节剂以对抗 AD的炎症成分无需越过血脑屏障。