Tetz George, Tetz Victor
Department of Neuroscience, Human Microbiology Institute, New York, NY 10128, USA.
Microorganisms. 2021 Jun 15;9(6):1301. doi: 10.3390/microorganisms9061301.
Alzheimer's disease is associated with prion-like aggregation of the amyloid β (Aβ) peptide and the subsequent accumulation of misfolded neurotoxic aggregates in the brain. Therefore, it is critical to clearly identify the factors that trigger the cascade of Aβ misfolding and aggregation. Numerous studies have pointed out the association between microorganisms and their virulence factors and Alzheimer's disease; however, their exact mechanisms of action remain unclear. Recently, we discovered a new pathogenic role of bacterial extracellular DNA, triggering the formation of misfolded Tau aggregates. In this study, we investigated the possible role of DNA extracted from different bacterial and eukaryotic cells in triggering Aβ aggregation in vitro. Interestingly, we found that the extracellular DNA of some, but not all, bacteria is an effective trigger of Aβ aggregation. Furthermore, the acceleration of Aβ nucleation and elongation can vary based on the concentration of the bacterial DNA and the bacterial strain from which this DNA had originated. Our findings suggest that bacterial extracellular DNA might play a previously overlooked role in the Aβ protein misfolding associated with Alzheimer's disease pathogenesis. Moreover, it highlights a new mechanism of how distantly localized bacteria can remotely contribute to protein misfolding and diseases associated with this process. These findings might lead to the use of bacterial DNA as a novel therapeutic target for the prevention and treatment of Alzheimer's disease.
阿尔茨海默病与淀粉样β（Aβ）肽的朊病毒样聚集以及随后错误折叠的神经毒性聚集体在大脑中的积累有关。因此，明确识别触发Aβ错误折叠和聚集级联反应的因素至关重要。众多研究指出微生物及其毒力因子与阿尔茨海默病之间存在关联；然而，它们确切的作用机制仍不清楚。最近，我们发现了细菌细胞外DNA的一种新致病作用，即触发错误折叠的Tau聚集体的形成。在本研究中，我们调查了从不同细菌和真核细胞中提取的DNA在体外触发Aβ聚集的可能作用。有趣的是，我们发现部分（而非全部）细菌的细胞外DNA是Aβ聚集的有效触发因素。此外，Aβ成核和延伸的加速程度会因细菌DNA的浓度以及该DNA所源自的细菌菌株而异。我们的研究结果表明，细菌细胞外DNA可能在与阿尔茨海默病发病机制相关的Aβ蛋白错误折叠过程中发挥了此前被忽视的作用。此外，它还揭示了一种新机制，即距离遥远的细菌如何远程促成蛋白质错误折叠以及与此过程相关的疾病。这些发现可能会促使将细菌DNA用作预防和治疗阿尔茨海默病的新型治疗靶点。
