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 大脑通过完善的肠-脑轴与胃肠道沟通。由于 随着年龄的增长，血脑屏障和肠上皮屏障的通透性增加， 变得更容易受到肠道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著增加。基于 根据这些数据，我们假设AD包括肠功能障碍，作为AD的一个主要未被认识的组成部分， 疾病此外，我们预计慢性疾病如IBD可能通过以下途径促进AD的进展： 炎症变化从肠道传播到大脑。我们将详细说明 使用AD的转基因小鼠模型，AppNL-G-F小鼠，在AD中的肠和脑。我们的假设是 通过完成三个目标进行测试。目的一是利用临床上可获得的精氨酸选择性T细胞抑制剂， 抗体减轻AppNL-G-F小鼠的基础AD肠道炎症和结肠炎诱导的恶化， 证实肠道功能障碍导致这些小鼠的记忆缺陷。第二个目标是评估 肠道选择性抑制性抗体治疗可降低脑Aβ水平、神经胶质增生、突触丢失和细胞因子 程度.最终的目标是将AppNL-G-F小鼠与Ltatm 1Dch小鼠杂交，Ltatm 1Dch小鼠携带α光毒素无效突变。 导致派伊尔淋巴结和淋巴结缺失。这种遗传方法将提供额外的 证实AppNL-G-F小鼠的肠道炎症变化是记忆功能障碍所必需的 大脑相关的变化。这项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，可以重新定位选择的免疫调节剂，以对抗免疫缺陷。 因此，本发明的组合物可用于治疗AD的炎性组分，而不需要穿过血脑屏障。