Bacterial Extracellular DNA Promotes β-Amyloid Aggregation

Abstract

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.

Transplantation of fecal microbiota from APP/PS1 mice and Alzheimer’s disease patients enhanced endoplasmic reticulum stress in the cerebral cortex of wild-type mice

“…Therefore, further exploration of these issues is also the next step of our study. Third, extracellular bacterial DNA has been shown to play an important role in protein misfolding ( Tetz et al, 2020 ; Tetz and Tetz, 2021 ), yet the current study did not analyze whether fecal transplantation increases extracellular bacterial DNA in plasma, so this will be a direction for our future research. Finally, the specific communication pathways between brain and gut microbiota are not fully understood, and how TMAO causes ER stress in the cerebral cortex is unclear, so more in-depth studies are needed to test and verify our findings.…”

Novel prokaryotic system employing previously unknown nucleic acids-based receptors

“…Moreover, given the recently discovered ability of DNA molecules to modify and misfold proteins, it is intriguing whether TezRs could possess a similar chaperoning function [32,[143][144][145]. Recently, we discovered the existence of a similar regulatory system in eukaryotes [45].…”

Lipopolysaccharide, Identified Using an Antibody and by PAS Staining, Is Associated With Corpora amylacea and White Matter Injury in Alzheimer's Disease and Aging Brain

“…We also found Gram-negative bacterial DNA in AD and aging brains. Recent studies demonstrated that bacterial DNA promotes aggregation of β-amyloid and tau, two hallmarks of AD pathology (Tetz et al, 2020 ; Tetz and Tetz, 2021 ). The DNA was derived from Porphyromonas gingivalis, Burkholderia burgdorferi , and different strains of E. coli , all of which are gram-negative and have been associated with AD (Tetz et al, 2020 ).…”