Rydbom Jerrik, Kohl Halea, Hyde Vanesa R, Lohr Kelly M
Department of Biology, Washington and Jefferson College, Washington, PA, United States.
Front Neurosci. 2021 Nov 2;15:731602. doi: 10.3389/fnins.2021.731602. eCollection 2021.
Tau is a microtubule-associated protein that stabilizes the neuronal cytoskeleton. In the family of neurodegenerative diseases known as tauopathies, including Alzheimer's disease (AD), frontotemporal dementia (FTD), and chronic traumatic encephalopathy (CTE), abnormal tau aggregation destabilizes microtubule structure, contributing to a cascade of cellular processes leading to neuronal cell death. The gut microbiome has increasingly become a target of neurodegenerative disease research since gut microbiome imbalances have been linked to protein aggregation and inflammation through a bidirectional axis linking the gut and brain. Accordingly, the present study examined tau-mediated changes to gut microbiome composition and immune activation in a model of human mutant tauopathy. Fecal deposit quantification and gastric emptying time courses suggested an abnormal food distribution and reduced gut motility in tau transgenic flies compared to controls. Tau transgenic flies also showed an increase in gut bacteria colony forming units (CFUs) from diluted fly homogenate, indicating an increased bacterial load. Finally, we showed that tau transgenic flies have a trend towards elevated systemic levels of antimicrobial peptides targeting gram-negative bacteria using qPCR, suggesting an enhanced innate immune response to bacterial insult. These data demonstrate qualifiable and quantifiable gut microbial and innate immune responses to tauopathy. Furthermore, these results provide a framework for future studies targeting the gut microbiome as a modifier of neurodegenerative disease.
tau蛋白是一种与微管相关的蛋白质,可稳定神经元细胞骨架。在被称为tau蛋白病的神经退行性疾病家族中,包括阿尔茨海默病(AD)、额颞叶痴呆(FTD)和慢性创伤性脑病(CTE),异常的tau蛋白聚集会破坏微管结构的稳定性,导致一系列细胞过程,最终导致神经元细胞死亡。肠道微生物群越来越成为神经退行性疾病研究的目标,因为肠道微生物群失衡已通过连接肠道和大脑的双向轴与蛋白质聚集和炎症联系起来。因此,本研究在人类突变tau蛋白病模型中研究了tau蛋白介导的肠道微生物群组成变化和免疫激活情况。粪便沉积定量和胃排空时间进程表明,与对照组相比,tau转基因果蝇的食物分布异常且肠道蠕动减弱。tau转基因果蝇稀释后的匀浆中肠道细菌集落形成单位(CFU)也有所增加,表明细菌载量增加。最后,我们通过qPCR表明,tau转基因果蝇针对革兰氏阴性菌的全身抗菌肽水平有升高趋势, 表明对细菌损伤的先天免疫反应增强. 这些数据证明了对tau蛋白病的肠道微生物和先天免疫反应具有可定性和可定量性. 此外, 这些结果为未来以肠道微生物群作为神经退行性疾病调节剂的研究提供了框架.