DNA from Bacteria in Brain May Promote Tau Clumping, Study Suggests

DNA from Bacteria in Brain May Promote Tau Clumping, Study Suggests
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DNA from various species of bacteria, some of which — like E. coli — have been identified in the brains of Alzheimer’s patients, can cause the tau protein to fold incorrectly and form the toxic, clump-like structures increasingly thought to play a key role in disease progression.

The study points to bacterial DNA as a potential initial cause of protein misfolding in Alzheimer’s, and suggests that targeting this DNA might be a way of not only treating the disease, but also preventing it.

“This study shows that bacterial DNA can promote tau aggregation in vitro [a lab study]. Many more studies need to be done to confirm and extend these observations in order to fully understand the potential role of bacterial DNA in the pathogenesis of Alzheimer’s disease,” Claudio Soto, a study author, said in a press release.

The study, “Bacterial DNA promotes Tau aggregation,” was published in the journal Scientific Reports.

Alzheimer’s is characterized by the formation of amyloid plaques and tau tangles in the brain, which disrupt communication between nerve cells and cause their death. These abnormal protein clumps have the ability to spread among cells, being a primary cause of disease progression.

While amyloid plaques have been seen as the most important disease-causing mechanism in Alzheimer’s, recent studies suggest that tau clumps also play a major role in disease progression.

Exactly what causes tau to misfold is not well-understood. However, growing evidence suggests that bacteria might be to blame. In fact, scientists have found that Alzheimer’s patients have higher levels of bacteria in their brains compared to the general population. And some species with these excessive levels may not only invade neurons but can also be found in the space within neurons — potentially explaining the presence of tau clumps both inside and outside the cells.

Researchers at the Human Microbiology Institute (HMI), a nonprofit research group, and the Mitchell Center for Alzheimer’s disease at the University of Texas McGovern Medical School in Houston looked at what happens to the tau protein when extracellular DNA from different species of bacteria is present.

When tau is cultured in specific conditions, researchers are able to produce tau clumps in the lab that are similar to those seen in patients, retaining their ability to spread, and causing seemingly normal and functional tau proteins to become improperly folded and to incorporate new aggregates.

The team tested if bacterial DNA could accelerate this clumping process, by mixing normal tau with extracellular DNA from  bacteria — including Pseudomonas aeruginosa, Tetzosporium hominis, Tetzerella alzheimeri, Escherichia or E. coli, Porphyromonas gingivalis, and Borrelia burgdorferi — and culturing them in those same conditions.

P. gingivalis, E. coli, and B. burgdorferi have all been detected in the brains or cerebrospinal fluid (CSF, the liquid surrounding the brain and spinal cord) of Alzheimer’s patients, while T. alzheimeri is a new species that has been identified in the mouth of an Alzheimer’s patient with gum inflammation.

The team found that several, but not all, bacterial species promoted tau clumping. The bacteria that accelerated the process the most were T. alzheimeri, and E. coli, while P. gingivalis and B. burgdorferi had only a moderate effect at promoting clumping.

They also tested DNA from Candida – a fungus also found in the central nervous system of some patients — and human cells for comparison. These had a much lower promoting effect than extracellular bacterial DNA.

The team then used different DNA amounts of E. coli and P. gingivalis — both of which have been found in damaged brain structures in Alzheimer’s patients and within neurons. They wanted to mimic the range of DNA concentrations found in the CSF of patients with different diseases (1-600 nanograms per milliliter), to determine if the amount of DNA influenced tau clumping.

Their findings suggested a dose-dependent effect, meaning that the higher the amount of DNA mixed with tau, the faster tau would misfold and aggregate.

“We found that DNA from various species of bacteria, some of which were previously identified in the CSF and brains of patients with AD [Alzheimer’s disease], can lead to tau protein misfolding and aggregation, suggesting their potential role in the initiation and progression of pathological abnormalities responsible for AD,” the researchers wrote.

Notably, the clumping effects disappeared when the DNA was digested with an enzyme, supporting the idea that the DNA is indeed accelerating tau clumping.

Of note, DNA from bacterial strains P. aeruginosa and T. hominis did not cause any significant aggregation. More research is needed to identify why some bacterial DNA causes aggregation and some does not.

“This is the first report to show that bacterial DNA plays a role in protein misfolding and aggregation, which may become a new target for the treatment of not just Alzheimer’s, but other neurogenerative diseases involving tau aggregation,” said George Tetz, the study’s lead investigator and head of research and development at HMI.

“For decades, scientists have been frustrated with clinical trials failures in the Alzheimer’s space. So, this is a whole new hypothesis — we may have found a principally new lead not only for treating Alzheimer’s, but also for its prevention,” Tetz added.

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Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência. Inês currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.

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