An international team of researchers from the United States, Australia, Poland, Norway, and New Zealand, has found higher levels of Porphyromonas gingivalis, a bacterium associated with chronic gum disease (periodontitis), and toxic enzymes from the bacterium called gingipains in the brains of patients with Alzheimer’s disease. The team has also designed and synthesized small-molecule inhibitors targeting gingipains: inhibition of gingipains reduced the bacterial load of an established Porphyromonas gingivalis brain infection, blocked production of amyloid beta, a component of the amyloid plaques commonly associated with Alzheimer’s disease, reduced neuroinflammation, and rescued neurons in the hippocampus.
“We now have strong evidence connecting Porphyromonas gingivalis and Alzheimer’s pathogenesis, but more research needs to be done,” said senior author Dr. Jan Potempa, a researcher at the University of Louisville School of Dentistry and Jagiellonian University in Poland.
“An even more notable aspect of this study is demonstration of the potential for a class of molecule therapies targeting major virulence factors to change the trajectory of Alzheimer’s disease, which seems to be epidemiologically and clinically associated with periodontitis.”
In animal models, oral Porphyromonas gingivalis infection led to brain colonization and increased production of amyloid beta.
Dr. Jan Potempa and co-authors found Porphyromonas gingivalis’ gingipains in the neurons of patients with Alzheimer’s disease.
Gingipains are secreted and transported to outer bacterial membrane surfaces and have been shown to mediate the toxicity of Porphyromonas gingivalis in a variety of cells.
The team correlated the gingipain levels with pathology related to two markers: tau, a protein needed for normal neuronal function, and ubiquitin, a small protein tag that marks damaged proteins.
Seeking to block Porphyromonas gingivalis-driven neurotoxicity, the scientists set out to design a series of small molecule therapies targeting gingipains.
In preclinical experiments, they demonstrated that by inhibiting the compound COR388, there was reduced bacterial load of an established Porphyromonas gingivalis brain infection, blocked amyloid beta production, reduced neuroinflammation and protected neurons in the hippocampus — the part of the brain that mediates memory and frequently atrophies early in the development of Alzheimer’s disease.
“Infectious agents have been implicated in the development and progression of Alzheimer’s disease before, but the evidence of causation hasn’t been convincing,” said lead author Dr. Stephen Dominy, Cortexyme co-founder and chief scientific officer.
“Now, for the first time, we have solid evidence connecting the intracellular, Gram-negative pathogen Porphyromonas gingivalis, and Alzheimer’s pathogenesis while also demonstrating the potential for a class of small molecule therapies to change the trajectory of disease.”
The findings appear in the journal Science Advances.
Stephen S. Dominy et al. 2019. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Science Advances 5 (1); doi: 10.1126/sciadv.aau3333