Investigating the strain-specific role of Bacteroides in the etiology of Alzheimer's disease

研究拟杆菌在阿尔茨海默病病因学中的菌株特异性作用

• 批准号: 10381224
• 负责人: Laura Michelle Cox
• 金额: $ 43.49万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10381224
• 关键词: APP-PS1; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Animal Model; Bacteria; Bacteroides; Bacteroides fragilis; Brain; Cell Wall; Chronic; Comparative Genomic Analysis; DNA Sequence Alteration; Data; Degradation Pathway; Diagnosis; Disease; Endoplasmic Reticulum; Etiology; Exhibits; Gene Expression; Genes; Genetic Transcription; Genomics; Histologic; Human; Impairment; In Vitro; Infectious Agent; Insulinase; Intestines; Lead; Measures; Memory; Metagenomics; Metronidazole; Microglia; Molecular; Mus; Nature; Neurons; Neurotransmitters; Pathogenesis; Pathway interactions; Phagocytosis; Play; Prevention; Process; Proteins; Research; Role; Senile Plaques; Shotguns; Signal Pathway; Testing; Tight Junctions; Toxin; Variant; Virulence Factors; acute infection; aged; base; fragilysin; gut microbiota; human disease; immunoreactivity; immunoregulation; in vitro Assay; in vivo; inflammatory disease of the intestine; insight; macrophage; microbiota; monocyte; mouse model; nervous system disorder; neuron loss; neurotoxicity; nonalzheimer dementia; novel; prevent; protein degradation; response; stool sample; systemic inflammatory response; tau Proteins; tau aggregation; tau phosphorylation; tau-1; transcriptomics

PROJECT SUMMARY While an infectious etiology has been proposed to be involved in the initiation and progression of Alzheimer’s disease (AD), more evidence is needed to support the roles of specific infectious agents and to identify mechanisms by which they act. Given the chronic nature of AD and based on our discoveries in animal models of AD, we hypothesize that a chronic and sub-acute infection with specific Bacteroides strains contributes to AD by affecting Ab and tau phosphorylation, aggregation, and clearance, and contributing to neuronal toxicity. In support of our hypothesis, we were the first group to demonstrate that Bacteroides not only correlated with Ab levels in the brain, but actually increased amyloid plaques when administered to animal models of AD. Strikingly, Bacteroides is elevated in AD, correlates with CSF levels of Ab42 and phospho-tau, and is associated with markers of gut inflammation in AD patients, suggesting a direct relevance to human disease. In our preliminary data, we found that B. fragilis affected cortical expression of genes involved in APP and tau phosphorylation that promote their aggregation, as well as genes related to memory and neuronal death. We also found that Bacteroides downregulated microglial genes important for the clearance of Ab. Depletion of Bacteroides with metronidazole decreased amyloid plaques, increased cortical expression of insulin degrading enzyme, which can degrade Ab, and affected genes involved in multiple protein degradation pathways. We found that Bacteroides could impair macrophage Ab phagocytosis in vitro and in vivo. Importantly, we found that transfer of human gut microbiota from AD patients into mice affected similar microglia genes involved in protein degradation and clearance, as well as pathways related to neuronal cell death, suggesting that the AD gut microbiota may harbor infectious agents that contribute to the disease process. Because Bacteroides species are highly prevalent in humans and exhibit a high degree of functional variation among strains, it is not likely that all Bacteroides contribute to AD. In this proposal, we will modify Koch’s postulates to detect Bacteroides strains associated with AD vs. healthy controls and non-AD dementia controls, isolate these strains in pure culture, and use in vitro assays to optimize strain selection for in vivo studies. We will then transfer AD-derived strains to WT mice and animal models of AD, measure AD pathology, and re-isolate our AD-derived strains to determine whether they play a causal role. To investigate potential mechanisms, we will also investigate whether AD strains can affect APP and tau aggregation and clearance, neuronal toxicity, or disrupt transcriptional networks in microglia and neurons. By investigating the molecular and functional diversity in Bacteroides in AD, our studies have the potential to identify novel pathogenicity factors in Bacteroides that could be used both for the diagnosis and treatment of AD.

项目摘要 虽然已经提出一种传染病学参与阿尔茨海默氏症的倡议和发展 疾病（AD），需要更多的证据来支持特定的传染剂的作用并确定 它们采取的机制。鉴于AD的慢性性质并根据我们在动物模型中的发现 在AD中，我们假设患有特定杀菌剂菌株的慢性和亚急性感染有助于AD 通过影响AB和TAU磷酸化，聚集和清除率，并导致神经元毒性。在 对我们的假设的支持，我们是第一个证明细菌的人，不仅与AB相关 大脑中的水平，但实际上会增加淀粉样蛋白斑块，用于AD动物模型。令人惊讶的是， AD中的杆菌升高，与CSF水平的AB42和磷酸-TAU相关，并且与 AD患者的肠道注射标记，表明与人类疾病有直接相关。在我们的初步中 数据，我们发现脆弱的B. vragilis影响了与APP和Tau磷酸化有关的基因的皮质表达， 促进它们的聚集以及与记忆和神经元死亡有关的基因。我们还发现 细菌下调的小胶质细胞基因对于清除AB很重要。用菌落耗尽 甲硝唑还原淀粉样斑块，增加的胰岛素降解酶的皮质表达，哪个 可以降解AB，并影响参与多种蛋白质降解途径的基因。我们发现 细菌可能会损害体外和体内巨噬细胞AB吞噬作用。重要的是，我们发现转移 来自AD患者的人类肠道微生物群的影响小鼠，影响了涉及蛋白质的类似小胶质细胞基因 降解和清除以及与神经元细胞死亡有关的途径，表明AD肠 微生物群可能具有导致疾病过程的传染剂。因为细菌的物种 在人类中非常普遍，并且在菌株之间表现出高度的功能变化，不可能 所有细菌均导致AD。在此提案中，我们将修改Koch的假设以检测细菌菌株 与AD与健康对照和非AD痴呆对照相关，将这些菌株隔离在纯文化中，以及 使用体外测定方法来优化体内研究的应变选择。然后，我们将将广告衍生的菌株转移到wt AD的小鼠和动物模型，测量AD病理学并重新分解我们的广告菌株，以确定 他们是否扮演因果角色。为了研究潜在机制，我们还将研究AD菌株是否 可以影响应用程序和TAU的聚合和清除，神经元毒性或中断转录网络 小胶质细胞和神经元。通过研究AD中菌烯的分子和功能多样性，我们的研究 有可能识别可用于诊断的细菌剂中新型致病因子 和AD的处理。