New York, NY (December 16, 2022) – A New-York city-based Human Microbiology Institute presented “Bacterial DNA promotes tau and beta-amyloid aggregation and is suggested as a novel therapeutic target for Alzheimer’s disease” at the Lancet Summit: Presymptomatic Prevention and Treatment of Neurodegenerative Diseases.
The biological paths that lead to Alzheimer’s disease and other neurodegenerative disorders start many years before clinical symptoms arise. In research settings, diagnostic criteria for these diseases now involve the use of biomarkers that reveal such pathophysiological changes.
Until now, the exact factor responsible for triggering seeded nucleation remained elusive. The suspicion that the seeding factor of AD might arise from microorganisms has been advanced by many groups. However, the identity of the microbial component that might trigger prionogenic transformation was unclear.
We investigated bacterial eDNA from various Gram-positive and Gram-negative oral pathogens associated with AD development, which might trigger Aβ and Tau misfolding. The invasion of the brain by bacteria enables the direct secretion of their extracellular DNA or release under certain conditions, such as prophage activation. This results in the release of bacterial DNA directly into the CNS, leading to a high local DNA concentration.
The monitoring of eDNA from different E. coli strains surprisingly showed that the catalysis of Aβ aggregation has DNA strain-specific characteristics. Thus, only the eDNA from some of the E. coli strains shortened the lag phase, whereas others did not affect it. Moreover, among the E. coli eDNA samples that did increase nucleation and shorten the lag-phase, only the eDNA of E. coli ATCC25922 potentiated elongation and increased ThT fluorescence intensity at the plateau.
Intriguingly, analysis of eDNA molecule size from different E. coli strains revealed no association between the eDNA band size of an E.coli strain and its effect on Aβ or tau aggregation. This suggests that the aggregation capacity of eDNA molecules is not only directly relevant to their length.
Overall, our data add another line of evidence that bacterial eDNA as a virulence factor might have additional pathogenic mechanisms through protein aggregation, which could lead to the future translational potential of this discovery.