Human Microbiology Institute, New York, NY, 10013, USA.
Tetz Laboratories, New York, NY, 10013, USA.
Sci Rep. 2020 Feb 11;10(1):2369. doi: 10.1038/s41598-020-59364-x.
A hallmark feature of Alzheimer's disease (AD) and other tauopathies is the misfolding, aggregation and cerebral accumulation of tau deposits. Compelling evidence indicates that misfolded tau aggregates are neurotoxic, producing synaptic loss and neuronal damage. Misfolded tau aggregates are able to spread the pathology from cell-to-cell by a prion like seeding mechanism. The factors implicated in the initiation and progression of tau misfolding and aggregation are largely unclear. In this study, we evaluated the effect of DNA extracted from diverse prokaryotic and eukaryotic cells in tau misfolding and aggregation. Our results show that DNA from various, unrelated gram-positive and gram-negative bacteria results in a more pronounced tau misfolding compared to eukaryotic DNA. Interestingly, a higher effect in promoting tau aggregation was observed for DNA extracted from certain bacterial species previously detected in the brain, CSF or oral cavity of patients with AD. Our findings indicate that microbial DNA may play a previously overlooked role in the propagation of tau protein misfolding and AD pathogenesis, providing a new conceptual framework that positions the compromised blood-brain and intestinal barriers as important sources of microbial DNA in the CNS, opening novel opportunities for therapeutic interventions.
阿尔茨海默病（AD）和其他 tau 病的一个显著特征是 tau 蛋白错误折叠、聚集和在大脑中的积累。有强有力的证据表明，错误折叠的 tau 聚集体具有神经毒性，导致突触丧失和神经元损伤。错误折叠的 tau 聚集体能够通过类似于朊病毒的接种机制在细胞间传播病理学。tau 错误折叠和聚集的起始和进展所涉及的因素在很大程度上尚不清楚。在这项研究中，我们评估了来自不同原核和真核细胞的 DNA 对 tau 错误折叠和聚集的影响。我们的结果表明，与真核 DNA 相比，来自各种不同的革兰氏阳性和革兰氏阴性细菌的 DNA 导致 tau 错误折叠更为明显。有趣的是，从以前在 AD 患者的大脑、CSF 或口腔中检测到的某些细菌中提取的 DNA 对促进 tau 聚集的作用更高。我们的发现表明，微生物 DNA 可能在 tau 蛋白错误折叠和 AD 发病机制的传播中发挥了以前被忽视的作用，为将受损的血脑和肠屏障作为中枢神经系统中微生物 DNA 的重要来源提供了一个新的概念框架，为治疗干预开辟了新的机会。
