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Deciphering the effect of human microbiota on Alzheimer's disease using C. elegans models of protein conformational diseases

使用蛋白质构象疾病的秀丽隐杆线虫模型解读人类微生物群对阿尔茨海默病的影响

基本信息

批准号：
10341111
负责人：
Daniel Milosz Czyz
金额：
$ 7.63万
依托单位：
UNIVERSITY OF FLORIDA
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：
2021-02-15 至 2024-01-31
项目状态：
已结题

项目摘要

Alzheimer’s disease (AD) is a fatal neurodegenerative disorder characterized by a progressive loss of memory and cognitive function due to protein misfolding and aggregation, a common feature among protein conformational diseases (PCDs). The exact factors that influence PCDs are not known; however, recent evidence suggests that bacteria may contribute to the pathogenesis of AD and other neurodegenerative diseases. To better understand the influence of bacteria on protein homeostasis (proteostasis), we are studying the effects of bacterial colonization of the Caenorhabditis elegans gut on protein aggregation in the intestine and other tissues. In a pilot screen of over 60 strains, we identified bacteria that can either increase or decrease protein aggregation not only in the intestine but throughout other tissues, including muscle, neurons, and gonad. We found that the bacteria that suppress protein aggregation have something in common—they produce butyrate. In follow-up experiments, we demonstrated that both exogenous and endogenous butyrate suppressed bacteria- mediated protein aggregation. These results suggest that intestinal bacteria affect host proteostasis and can potentially contribute to the pathogenesis of AD. Collectively, our preliminary data reveal a possible causative role for bacteria in diseases that are characterized by protein aggregation. As such, we propose to further investigate the effect of bacteria on proteostasis using C. elegans models by: (I) determining the impact of intestinal colonization by all human microbiome bacterial isolates on host proteostasis and pathogenesis of AD, and (II) observing the effect of exogenous and endogenous butyrate on bacteria that enhance protein aggregation. Deciphering the effect that bacteria have on host proteostasis will ultimately provide a basis for the development of prophylactics, therapeutics, and biomarkers.

阿尔茨海默病(AD)是一种致命的神经退行性疾病，其特征是进行性丧失蛋白质错误折叠和聚集引起的记忆和认知功能，这是蛋白质的共同特征构象疾病(PCDS)。影响PCDS的确切因素尚不清楚；然而，最近有证据表明，细菌可能与阿尔茨海默病和其他神经退行性疾病的发病有关疾病。为了更好地了解细菌对蛋白质稳态的影响，我们正在研究线虫肠道细菌定植对肠道蛋白质聚集的影响其他纸巾。在60多个菌株的初步筛选中，我们确定了可以增加或减少蛋白质的细菌。不仅在肠道内聚集，而且在其他组织中聚集，包括肌肉、神经元和性腺。我们发现抑制蛋白质聚集的细菌有一个共同点--它们产生丁酸盐。在后续的实验中，我们证明了外源和内源丁酸都能抑制细菌-- 介导的蛋白质聚集。这些结果表明，肠道细菌影响宿主蛋白平衡，并可以可能在AD的发病机制中起作用。总而言之，我们的初步数据揭示了一个可能的原因细菌在以蛋白质聚集为特征的疾病中的作用。因此，我们建议进一步使用线虫模型研究细菌对蛋白平衡的影响：(I)确定细菌对蛋白质平衡的影响全人类微生物组细菌在肠道内定植对宿主蛋白平衡和AD发病机制的影响以及(Ii)观察外源和内源丁酸对提高蛋白质的细菌的影响聚合。破译细菌对宿主蛋白平衡的影响最终将为预防药物、治疗药物和生物标志物的发展。