An oral pathogenic bacterium can lead to the pathology of Alzheimer's disease | Drug

An international team of researchers from the United States, Australia, Poland, Norway and New Zealand found higher rates of Porphyromonas gingivalis, a bacterium badociated with chronic gum disease (periodontitis) and toxic enzymes of the bacterium called gingipain in the brains of patients with Alzheimer's disease. The team also designed and synthesized small molecule inhibitors targeting gingipaines: inhibition of gingipains reduced the bacterial burden of Porphyromonas gingivalis brain infection, blockage of beta-amyloid production, component of amyloid plaques generally badociated with Alzheimer's disease, decreased neuroinflammation and neurons saved in the hippocampus.

Porphyromonas gingivalisGingipains (red) among neurons in the brain of a patient with Alzheimer's disease. Image credit: Cortexis.

"We now have strong evidence linking Porphyromonas gingivalis and the pathogenesis of Alzheimer's, but further research is needed, "said Dr. Jan Potempa, lead author, researcher at the School of Dentistry at the University of Louisville and at Jagiellonian University in Poland.

"An even more remarkable aspect of this study is the demonstration of the potential of a clbad of molecular therapies targeting major virulence factors to alter the trajectory of Alzheimer's disease, which appears to be badociated epidemiologically and clinically with periodontitis."

In animal models, oral Porphyromonas gingivalis the infection led to colonization of the brain and increased production of beta-amyloid.

Dr. Jan Potempa and co-authors found Porphyromonas gingivalis'Gingipains in the neurons of patients with Alzheimer's disease.

Gingipaines are secreted and transported to the outer membrane surfaces of the bacterial membrane. It has been shown that they induce the toxicity of Porphyromonas gingivalis in a variety of cells.

The team correlated gingipain levels with a pathology related to two markers: tau, a protein needed for normal neuronal function, and ubiquitin, a small protein label that marks damaged proteins.

Seeking to block Porphyromonas gingivalisneurotoxicity, scientists decided to design a series of small molecule therapies targeting gingipain.

In preclinical experiments, they demonstrated that by inhibiting the COR388 compound, there was a reduction in the bacterial load of a Porphyromonas gingivalis cerebral infection, blockage of beta-amyloid production, reduction of neuroinflammation and protection of neurons in the hippocampus – part of the brain responsible for memory and frequent atrophies in early development of Alzheimer's disease.

"Infectious agents have already been implicated in the development and progression of Alzheimer's disease, but evidence of the cause-and-effect relationship has not been convincing," said Dr. Stephen Dominy, lead author, the co-founder of Cortexme and scientific leader.

"Now, for the first time, we have strong evidence linking the intracellular Gram-negative pathogen. Porphyromonas gingivalisand the pathogenesis of Alzheimer's, while demonstrating the potential of a clbad of small molecule therapies to alter the trajectory of the disease. "

The results appear in the log Progress of science.

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Stephen S. Dominy et al. 2019. Porphyromonas gingivalis in brains with Alzheimer's disease: Evidence on causality and treatment with small molecule inhibitors. Progress of science 5 (1); doi: 10.1126 / sciadv.aau3333