A type of mouth bacteria involved in gum disease is able to infect human brain cells, new research shows. The infection results in cellular changes that are similar to what is seen in Alzheimer’s, supporting a link between the bacteria and the neurodegenerative disease.
The findings were presented at the Advances in Alzheimer’s and Parkinson’s Disease (AAT-AD/PD) Focus Meeting 2020, recently held virtually, in a poster titled, “Intracellular Porphyromonas gingivalis in Neuron-astrocyte-microglia Co-cultures Results in Alzheimer’s disease-like Phenotype.”
Porphyromonas gingivalis is a type of bacteria best known as a cause of gum (periodontal) disease. However, this bacteria in recent years also has been implicated in Alzheimer’s disease (AD). It produces toxins called gingipains, which have been detected in more than 90% of post-mortem Alzheimer’s brains. Additionally, studies in mice have shown that P. gingivalis infection can spread to the brain and cause changes similar to what is seen in AD.
The team used human inducible pluripotent stem cells (iPSCs) in their research. iPSCs can be created from other human cells, like skin cells, and can be induced to grow into almost any other cell type once provided with specific biochemical cues. In this case, the researchers used iPSCs to produce human neurons. Then, they infected these neurons with P. gingivalis.
The scientists demonstrated that the bacteria could get into these neurons. Once there, the bacteria secreted gingipains, and induced Alzheimer’s-like changes in the neurons, or nerve cells. This included the accumulation of digestive bodies called autophagic vacuoles.
These changes were “reminiscent of ultrastructure found in dystrophic neurites [damaged neurons] in AD brains,” the researchers wrote.
The team also conducted a similar experiment using induced neurons together with different types of glia — the “support cells” of the brain — which have multiple functions including regulating inflammation. In these experiments, the bacteria induced an inflammatory reaction. Since brain inflammation has been implicated in Alzheimer’s, these data further support a link between the bacteria and the disease.
“Over the past several years, Cortexyme and scientists around the world have been publishing evidence on the role of P. gingivalis in Alzheimer’s disease,” Stephen Dominy, MD, Cortexyme’s co-founder, chief scientific officer, and one of the co-authors of the poster, said in a press release.
“Our goal is to continue to understand the unique ability of this pathogen to induce cellular damage related to Alzheimer’s disease, and how we can best target it to treat the disease,” Dominy said. “With this latest evidence of P. gingivalis infection of brain cells in vitro, we are seeing verification that the pathogen is able to infiltrate neurons and catalyze the corresponding characteristic pathology, reinforcing the fact that this is an essential upstream target for Alzheimer’s treatment.”
The findings also support the idea that treatments targeting P. gingivalis could have therapeutic benefit in Alzheimer’s.
Cortexyme is currently developing an investigational Alzheimer’s therapeutic candidate called COR388, which is an inhibitor of gingipains. COR388 was found to be safe and well-tolerated in a Phase 1 clinical trial (NCT03331900) conducted in healthy volunteers.
Its efficacy, safety, and tolerability in people with Alzheimer’s is now being investigated in the Phase 2/3 clinical trial GAIN (GingipAIN Inhibitor for Treatment of Alzheimer’s Disease; NCT03823404). The GAIN trial is currently recruiting participants at multiple locations in the United States and Europe. Additional information can be found here.
“The Phase 2/3 GAIN Trial of COR388 is supported by years of research that the neurodegeneration associated with Alzheimer’s may be caused by a bacterium and the gingipains it releases within the central nervous system,” said Casey Lynch, co-founder, CEO, and chair Cortexyme.
“The data presented [at the AAT-AD/PD meeting] adds to the preclinical and clinical evidence supporting our approach to this devastating disease,” Lynch said. “We are committed to optimizing the therapeutic potential of COR388 and the potential benefits this approach could have for the millions of people affected by Alzheimer’s disease.”
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