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University of Louisville researcher Jan Potempa and a team of international scientists led by the pharmaceutical company Cortexyme Inc. recently made headlines for their research on a possible connection between chronic gum disease and Alzheimer’s disease.

Potempa provided insight into their research in a Q&A with Insider Louisville.

Q. In layman’s terms, how does P. gingivalis (Pg), the common bacteria associated with chronic gum disease, influence the development of Alzheimer’s disease (AD)?

A. Gum disease, through its microbes, may contribute to the development of Alzheimer’s disease.

P. gingivalis, a so-called “keystone oral pathogen,” can convert good, commensal bacteria living in dental plaque, or biofilm, into bad guys. Local inflammation occurs, eroding structures supporting teeth. The systemic inflammation associated with chronic gum disease may contribute to the development or severity of Alzheimer’s, which is now believed to be an inflammatory disease of the brain.

Apart from this indirect link, Pg and a cohort of other oral bacteria, or their toxic products, can easily enter the circulation, and if they bridge the blood-brain barrier, they can cause inflammatory havoc in the brain. Finally, oral bacteria and their products may find the way into the brain along nerves.

Q. How do people acquire Pg? Please explain further how it gets from the mouth to the brain.

University of Louisville researcher Jan Potempa is with the Department of Oral Immunology and Infectious Diseases in the School of Dentistry. | Courtesy of UofL

A. People are colonized by Pg in their late teenage time, usually picking it up from adults (which might occur through sharing utensils or kissing, for example). In healthy individuals with appropriate oral health, Pg will stay in low numbers and do no harm.

However, in some individuals with yet unknown genetic risk factors, Pg will start growing in numbers, triggering a host defense response to which the bacterium is resistant.

This leads to eradication of good, commensal bacteria and conversion of others into dysbiotic ones that proliferate on the tooth surface below the gum line, resulting in an inflammatory reaction (red swollen gums, pus, bleeding, etc.).

In people with severe periodontitis, basic activities, such as chewing and tooth-brushing, release bacteria, including Pg into the bloodstream. From there, Pg can cross the blood-brain barrier in different ways. For example, directly through the barrier, which is getting less leak-tight in old people, or using immune mobile cells as Trojan horses, or via infections of cells lining the blood vessels in the brain. Finally, Pg may travel along nerves stretching from the oral cavity into the brain.

Q. I thought Alzheimer’s disease was tied to the development of plaques and tangles in the brain. Does Pg have any effect on or connection to those?

A. Development of AD is strongly linked to plaques and tangles in the brain. It was believed that these pathological structures suffocated neurons, causing the brain to malfunction. Recently, it is getting accepted that plaques and tangles are a response to inflammation in the brain. If Pg itself, or its toxins, get into the brain, they will trigger inflammation and, in consequence, lead to formation of plaque and tangles.

Q. Should people practice better oral hygiene to potentially reduce their risk of Alzheimer’s disease?

A. Yes, but it is not enough to brush and floss. In some individuals, professional tooth surface cleaning, especially below the gum line is necessary to avoid development of the gum disease.

Q. How might your team’s investigation further the research and development of new drugs for treating Alzheimer’s disease or other forms of dementia?

A. Our results showed the presence of Pg toxins in the Alzheimer’s-affected brain. In separate animal experiments, we have shown that Pg, or its toxins, injected into the mouse brain cause tangles and plaques to form. Therefore, disabling Pg’s ability to migrate into the brain, or even better, eradicating Pg from people’s mouths, should prevent development or reduce severity of associated gum diseases and disorders, including Alzheimer’s. This is possible by targeting Pg toxins, which the bacterium needs to defend itself against attack by human antibacterial forces as well as to manipulate the commensal bacterial flora on the tooth surface to make them pathogenic.

Q. What is COR388, and what is its role in your research?

A. This small molecule specifically targets Pg toxins, blocking their malicious activity. In our research, using an animal model of oral infection, we have shown that COR388 efficiently prevents Pg dissemination into the brain.

Q. Because of your study, should everyone with gum disease assume they will go on to develop Alzheimer’s disease?

A. Far more research is needed to firmly link gum disease as a reason or cause for Alzheimer’s. AD is a complex, multifactorial disease, with a process that’s still not very well understood, that eats away at cognitive functions of the brain. Gum disease, through its microbes, may contribute to the development of AD and the transition of Pg from the mouth to the brain could be one way. We need to remember, however, that our mouth, especially bacterial biofilm below the gum line, is home to at least 250 bacterial species. Indeed, other researchers found corkscrew-like oral bacteria related to the one responsible for syphilis (Treponema palladium) in AD brains. Also, some fungus and viruses occur in the AD brain.

Q. Has your team estimated how much chronic gum disease increases the risk of Alzheimer’s disease? Or is it too early for that?

A. It is far too early for such an estimation. Gum disease is a risk factor, but there’s likely to be a myriad of yet unknown environmental factors and other factors.

Q. What additional work is needed to establish a definitive link?

A. Finding Pg and/or its products at a much higher frequency in Alzheimer’s-affected brains than in the brains of age-matched mentally healthy individuals is a good indication that this bacterium may contribute to AD. This is supported by the research on animal models. … However, further research would need to show eradication of Pg or blocking its ability to get into the brain (by vaccination or therapeutic compounds) prevents AD development. …In the case of Alzheimer’s disease, COR388 is a good start to show that Pg may be responsible for dementia, but a lot of work is needed to prove this contention.