About This Project

Alzheimer’s disease (AD) is associated with prion-like aggregation of the β-amyloid and Tau proteins, that form neurotoxic aggregates in the brain. Studies have pointed out the association between brain-localized bacteria and AD; however. Recently, we identified that bacterial DNA can aggregate Tau protein (Tetz et a, 2020). We will explore whether DNA from brain-localized bacteria triggers β-amyloid misfolding; thus, being, a previously overlooked cause of AD.

Ask the Scientists

What is the context of this research?

Developing a novel anti-AD drugs is limited by the lack of a clear understanding of the seeding factor that triggers the cascade of AD, and is reflected by the numerous failures of anti-AD drugs in the clinical trials.

Numerous studies have pointed out the association between brain-localized microorganisms and their virulence factors and AD; however, their exact mechanisms of action remain unclear. Recently, we discovered a new pathogenic role of bacterial extracellular DNA as a virulence factor in protein aggregation. Here, we are taking a new approach, evaluating bacterial extracellular DNA that is present in CSF and postmortem brains of individuals with AD as a novel therapeutic target for the prevention and treatment of AD.

What is the significance of this project?

AD is the most common cause of dementia worldwide and is a leading cause of death in elderly in the developed world, impacting many of our loved ones.

We launched this project because our previous data proved bacterial DNA engagement in aggregation of Tau protein that is another AD-associated protein (Tetz et al 2020). Given the central role played by misfolded β-amyloid in AD it is critical to clearly identify the seeding factor that triggers the cascade of β-amyloid misfolding (Chimon et al 2007). Our discovery that bacterial DNA could play a role in β-amyloid misfolding will pave the way for the future translational potential of this discovery to fight AD and would become a new frontier in AD research.

What are the goals of the project?

The ultimate goal of this project is to prove that bacterial DNA isolated from brain-localized bacteria could induce the seeding of Aβ misfolding. Extracellular DNA will be extracted from the matrix of different brain-localized bacteria. To prepare aggregated β-amyloid for seeding experiments, monomeric aggregate-free β-amyloid will be used (Soto et al 2015). For these studies we will incubate monomeric β-amyloid with DNA of different bacteria and measure Thioflavin T (ThT) fluorescence as a function of time in the ThT assay. We will also study the dose-dependent effect of DNA from certain bacteria on Aβ aggregation. Results will be published and will be made available to the whole scientific community. Results will serve as pilot data for future grant applications