The complex relationship between the microbiome and the rest of the body has only recently started to become truly appreciated. The bacteria of the gut are increasingly looking like a potential player in aging, and some bacteria in the mouth associated with chronic periodontitis may be linked to Alzheimer’s disease .
University of Louisville researcher Jan Potempa from the Department of Oral Immunology and Infectious Diseases in the School of Dentistry led a team of scientists in a new study, which demonstrated that the bacteria Porphyromonas gingivalis (P. gingivalis), the main pathogen involved in chronic periodontitis, is also found in the brains of Alzheimer’s disease patients. Chronic periodontitis is a common oral disease that is characterized by the chronic inflammation of periodontal tissues, which is provoked by the accumulation of excessive dental plaque.
It has been suggested before that there may be an infectious element to Alzheimer’s disease, but, until recently, the evidence has been limited . These researchers suggest that their study is strong evidence for a connection between the presence of P. gingivalis and the onset of Alzheimer’s disease.
During the study, the researchers showed that P. gingivalis infection in mice led to subsequent colonization of the brain by the bacteria and an increased level of amyloid beta, a primary part of the plaques that kill the neurons in Alzheimer’s disease.
The researchers also discovered that the harmful enzymes, known as gingipains, secreted by P. gingivalis were also present in the neurons of patients with Alzheimer’s disease. These enzymes, once secreted, are transported to the bacterial membrane surfaces, where they regulate the toxicity of P. gingivalis.
The levels of these secreted enzymes are directly correlated with the levels of tau, a protein required for the correct function of neurons, and ubiquitin, a protein that indicates the presence of the damaged and misfolded proteins typical in Alzheimer’s disease.
Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer’s disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer’s patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalis infection in mice resulted in brain colonization and increased production of Aβ1–42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function.
Perhaps the most interesting part of this study involved blocking the activity of the enzymes secreted by P. gingivalis in order to reduce the microbial burden in the brain. Blocking the enzymes prevented amyloid-beta production, reduced neuroinflammation, and rescued neurons in the hippocampus, the part of the brain that typically wastes away during the progression of the disease and that is responsible for memory.
The researchers used the drug COR388, which inhibits the target enzymes of P. gingivalis and was successfully used in a Phase 1b clinical trial, the results of which were announced in October 2018. The initial results showed that the drug improved the performance of Alzheimer’s patients on cognitive tests.
To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ1–42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer’s disease.
Cortexyme, the developer of COR388, recently announced that it plans to start Phase 2 and 3 clinical trials of the drug for mild to moderate Alzheimer’s disease sufferers in Q2 2019; please check the U.S. Clinical Trials website for updates beginning in February. You can also request more information about the trials here.
Our relationships with the bacteria that live within us are only really starting to be appreciated, and this study is another interesting development in the story of Alzheimer’s disease. It may be the case that this and similar diseases are driven by an infectious bacterial element, and eradicating these bacteria or blocking their activity may lead to progress in combating these devastating diseases.
Until such drugs are available, it would be wise to pay particular attention to your oral health and avoid the development of chronic periodontitis and other conditions that lead to a rise in chronic inflammation, known as ‘inflammaging’, which appears to contribute to aging.
 Stephen S. Dominy, Casey Lynch, Florian Ermini, Malgorzata Benedyk, Agata Marczyk, Andrei Konradi, Mai Nguyen, Ursula Haditsch, Debasish Raha, Christina Griffin, Leslie J. Holsinger, Shirin Arastu-Kapur, Samer Kaba, Alexander Lee, Mark I. Ryder, Barbara Potempa, Piotr Mydel, Annelie Hellvard, Karina Adamowicz, Hatice Hasturk, Glenn D. Walker, Eric C. Reynolds, Richard L. M. Faull10, Maurice A. Curtis, Mike Dragunow, and Jan Potempa (2019). Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Science Advances, Vol. 5, no. 1, eaau3333, DOI: 10.1126/sciadv.aau3333.
 Gaur, S., & Agnihotri, R. (2015). Alzheimer’s disease and chronic periodontitis: Is there an association?. Geriatrics & gerontology international, 15(4), 391-404.