Key News in Family Medicine January 28, 2019 (3 ​​of 4)

In a new study, researchers have discovered that a bacterium largely responsible for gum disease also contributes to the development of Alzheimer's disease.

According to data from the National Institute of Dental and Craniofacial Research, 8.52% of American adults aged 20 to 64 years suffer from periodontitis (gum disease). Gum disease is a widespread problem that can have more negative consequences, ranging from tooth loss to increased cancer risk. New evidence now suggests that one of the bacteria involved in periodontitis could also contribute to the accumulation of toxic proteins in the brain, which scientists have badociated with the development of Alzheimer's disease.

These findings are from a new mouse study conducted by researchers at Cortexyme, Inc., a pharmaceutical company that aims to develop new treatments for Alzheimer's disease. The results of the research, whose lead author is Dr. Stephen Dominy, co-founder of Cortexyme, are published in the journal Progress of science.

"Infectious agents have already been implicated in the development and progression of Alzheimer's disease, but evidence of the cause-and-effect relationship is unconvincing," notes Dr. Dominy.

The bacterium that stimulates brain toxicity

The researchers targeted a bacterium …Porphyromonas gingivalis-which is an oral Gram-negative anaerobic that promotes the development of gum disease. P. gingivalis, note the researchers, also appears in the brains of people who have been diagnosed with Alzheimer's disease, which left the investigators intrigued.

Looking at a mouse model, the team discovered that infection with P. gingivalis leads to greater production of beta-amyloid in the rodent brain. Beta-amyloid is a marker of Alzheimer's disease in the brain; in this neurodegenerative state, the toxic protein accumulates in excess, forming plaques that disrupt normal communication between brain cells.

The researchers also examined gingipain, the toxic enzymes of P. gingivalis. They discovered that they could badociate high levels of gingipain with the presence of two other proteins that scientists have already badociated with the development of Alzheimer's disease – both in the human brain and in models murines -: tau and ubiquitin. The researchers explain that, in in vivo and in vitro models, gingipain exacerbated the toxicity of tau protein. However, once they chose the gingipain as a clinical target, the team was able to start developing strategies to counteract their effects.

A promising clinical target

Dr. Dominy and colleagues then developed a series of small molecule therapies blocking P. gingivalis gingipains. In experiments on murine models, the researchers finally identified a compound called "COR388" as the most effective gingipain inhibitor. COR388 has been able to reduce the presence of P. gingivalis in the brain after infection with this bacterium, which reduced neuroinflammation. The compound also stopped the production of toxic beta-amyloid and had a protective effect on the neurons of the hippocampus, the region of the brain largely responsible for memory-related processes.

"Now, for the first time, we have strong evidence linking the intracellular to gram-negative pathogen,[[[[P. gingivalis], as well as the pathogenesis of Alzheimer's, while demonstrating the potential of a clbad of small molecule therapies to alter the trajectory of the disease, "says Dr. Dominy.

"Despite significant funding and best efforts from academia, industry and lobby groups, clinical progress in the fight against Alzheimer's disease has been extremely slow" , adds Casey Lynch, co-author of the study.

"The Progress of science This publication highlights an unexpected factor in the pathology of Alzheimer's – the bacterium commonly badociated with chronic periodontal disease – and details the promising therapeutic approach that Cortexine is taking to address it with COR388. "

Casey Lynch

COR388 is already being tested and researchers have indicated that volunteers, whether healthy or diagnosed with Alzheimer's disease, have so far responded well to this compound. The Cortexis team is looking at organizing a larger clinical trial, testing the effect of COR388 in people with mild-to-moderate Alzheimer's disease this year.