Protection from Mucosal Pathology by Gut Microbiota during Experimental Colitis

项目总结/摘要 阿尔茨海默氏病（AD）是一种破坏性的神经退行性疾病，其特征在于进行性阿尔茨海默病（AD）是一种神经退行性疾病， 认知和功能障碍，最终导致记忆丧失。大多数AD病例是迟发性的， 零星的，没有证据表明孟德尔遗传模式，这表明一个重要的作用， 环境对疾病发作和/或进展的影响。目前还没有有效的治疗方法可以减缓， 停止或逆转AD的症状，而目前批准的药物治疗仅提供适度的， 短暂的好处。此外，许多最近的药物试验未能达到其溶解标志物的终点 AD大脑中的斑块或改善记忆。据信导致AD的病理后果 涉及淀粉样β肽（Aβ）在神经元中的积累，随后是神经胶质细胞的沉积。 缠结，其导致特定脑中突触和神经元功能障碍和神经元死亡的发作 地区AD病理学的特征在于循环免疫细胞中的炎性应答和免疫细胞中的炎性应答。 大脑的常驻免疫细胞，称为小胶质细胞。有趣的是，最近的研究表明， 的AD患者与匹配的健康对照不同，并且小鼠模型中的抗生素治疗 影响Aβ病理学和免疫反应。值得注意的是，微生物组调节许多免疫细胞类型 在整个身体。我们的实验室已经发现了防止炎症的特定细菌分子， 确定了免疫细胞中介导抗炎作用的受体和信号通路， 揭示了宿主-微生物相互作用如何改善几种小鼠模型的炎症状况。 这些主要预付款由NIDDK的母公司R 01提供资金。本行政补充文件 建议利用我们对特定肠道微生物分子的突破性研究， 炎症特性来测试AD的新疗法。具体目标1将描述粘膜免疫 反应，在前所未有的细节，在两个完善的小鼠模型的AD。此外，我们将确定， 实验性肠道炎症加速或加重小鼠的AD样病理和症状。具体 aim 2将专注于通过用肠道细菌分子抑制炎症来测试AD的新疗法， 预防和治疗肠道炎症。正在测试的创新假设是粘膜炎症 导致小鼠模型中AD样病理和行为以及抗炎免疫的激活 细胞的肠道细菌改善学习和记忆缺陷。验证这一概念，并发现 潜在的作用机制，将降低进一步研究AD中肠-脑连接的风险，并推动 令人兴奋的可能性是，利用肠道微生物组可能会导致安全有效的治疗选择， 阿尔茨海默氏症是当代和未来几代人最大的医学问题之一。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that is characterized by progressive cognitive and functional impairment, and ultimately memory loss. Most cases of AD are late-onset and sporadic, with no evidence for a Mendelian pattern of inheritance, suggesting a significant role for environmental contributions to disease onset and/or progression. There are no validated treatments that slow, halt or reverse the symptoms of AD, and currently approved pharmacotherapies provide only modest and transient benefits. Further, many recent drug trials have failed to meet their endpoints of dissolving hallmark plaques in the AD brain or improving memory. The pathological consequences leading to AD are believed to involve accumulation of the amyloid-β peptide (Aβ) in neurons followed by the deposition of neurofibrillary tangles, which result in the onset of synaptic and neuronal dysfunction and neuronal death in specific brain regions. AD pathology is characterized by an inflammatory response in circulating immune cells and in the brain's resident immune cells, known as microglia. Intriguingly, it has recently been shown that the microbiome of AD patients differs from that of matched healthy controls, and that antibiotic treatment in mouse models impacts Aβ pathology and immune responses. Notably, the microbiome regulates numerous immune cell types throughout the body. Our laboratory has discovered specific bacterial molecules that prevent inflammation, identified receptors and signaling pathways in immune cells that mediate anti-inflammatory effects, and revealed how host-microbial interactions can ameliorate inflammatory conditions in several mouse models. These major advances have been funded by the parent R01 from NIDDK. This Administrative Supplement proposes to leverage our ground-breaking studies of specific gut microbial molecules with potent anti- inflammatory properties to test novel treatments for AD. Specific Aim 1 will profile the mucosal immune response, in unprecedented detail, in two well-established mouse models of AD. Further, we will determine if experimental gut inflammation accelerates or exacerbates AD-like pathologies and symptoms in mice. Specific aim 2 will focus on testing novel therapies for AD by suppressing inflammation with gut bacterial molecules that prevent and treat intestinal inflammation. The innovative hypothesis being tested is that mucosal inflammation contributes to AD-like pathologies and behaviors in mouse models, and activation of anti-inflammatory immune cells by gut bacteria ameliorates learning and memory deficits. Validation of this concept, and discovery of underling mechanisms of action, will de-risk further research into the gut-brain connection in AD, and advance the exciting possibility that harnessing the gut microbiome may lead to safe and effective therapeutic options for Alzheimer’s disease, one of the greatest medical concerns of current and future generations.