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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

基本信息

批准号：
10612978
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
项目类别：
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/10612978
关键词：
APP-PS1 Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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 Infection Infectious Agent Insulinase Intestines Macrophage 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 aged fragilysin gut inflammation gut microbiota human disease immunoreactivity immunoregulation in vitro Assay in vivo insight metatranscriptomics 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-1 transcriptomics

项目摘要

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.

项目总结虽然感染性病因学被认为与阿尔茨海默氏症的发生和发展有关疾病(AD)，需要更多的证据来支持特定感染源的作用并确定他们采取行动的机制。鉴于阿尔茨海默病的慢性性质，以及我们在动物模型中的发现对于AD，我们假设特定菌株的慢性和亚急性感染与AD有关通过影响抗体和tau的磷酸化、聚集和清除，并促进神经元毒性。在……里面支持我们的假设，我们是第一个证明类杆菌不仅与抗体相关的小组在阿尔茨海默病动物模型中应用时，大脑中的淀粉样斑块实际上增加了。令人惊讶的是，类杆菌在AD中升高，与脑脊液中AB42和磷酸化tau的水平相关，并与 AD患者肠道炎症的标记物，提示与人类疾病直接相关。在我们的预赛中数据，我们发现脆弱芽孢杆菌影响了与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相关的基因。我们还发现，类杆菌下调了对抗体清除至关重要的小胶质细胞基因。类杆菌的枯竭作用甲硝唑减少淀粉样斑块，增加皮质胰岛素降解酶的表达，从而可降解抗体，并影响参与多种蛋白质降解途径的基因。我们发现类杆菌在体外和体内均能抑制巨噬细胞抗体的吞噬功能。重要的是，我们发现转移将人类肠道微生物区系从AD患者转移到受小鼠小胶质细胞相似基因影响的蛋白质中降解和清除，以及与神经细胞死亡相关的途径，表明AD肠道微生物区系可能含有促成疾病过程的感染性病原体。因为类杆菌属物种在人类中高度流行，并在不同菌株之间表现出高度的功能变异，因此不太可能所有类杆菌都与AD有关。在这项提案中，我们将修改科赫的假设以检测类杆菌菌株与AD与健康对照和非AD痴呆对照相关联，在纯培养中分离这些菌株，并使用体外试验来优化体内研究的菌株选择。然后我们将AD衍生的菌株转移到WT AD的小鼠和动物模型，测量AD的病理，并重新分离我们的AD衍生菌株以确定它们是否起到了因果作用。为了研究可能的机制，我们还将调查AD菌株可影响APP和tau的聚集和清除，神经元毒性，或扰乱转录网络小胶质细胞和神经元。通过研究AD中类杆菌的分子和功能多样性，我们的研究有可能确定新的致病因子，这些致病因子既可用于诊断以及AD的治疗。