Porphyomonas gingivalis, a bacteria that causes a type of gum disease known as chronic periodontitis, was found in the brains of Alzheimer’s patients, providing evidence of its possible role in the disease’s development, a study reports.
The release of toxic enzymes from this bacteria was blocked by a particular inhibitor that is currently in clinical studies, which reduced neuroinflammation and stopped the accumulation of Alzheimer’s-related beta-amyloid protein, according to the researchers.
Chronic periodontitis and infection with Porphyomonas gingivalis have been identified as significant risk factors for developing beta-amyloid plaques, dementia, and Alzheimer’s disease.
In a mouse model of Alzheimer’s disease with P. gingivalis gum disease, scientists observed impaired cognition and an increased buildup of Alzheimer’s-like plaques. Additionally, molecules present in the outer membrane of this bacteria have been found in the brains of human Alzheimer’s patients, suggesting that this type of bacterial infection may contribute to the development of Alzheimer’s.
P. gingivalis produces toxic enzymes known as gingipains, which can mediate the toxicity of P. gingivalis in different cells. Blocking gingipains decreases the bacteria’s ability to cause disease.
In a study funded by Cortexyme, researchers investigated whether P. gingivalis infection played a role in Alzheimer’s disease mechanisms through the secretion of gingipains to promote neuronal damage.
Researchers analyzed human postmortem brain tissue — obtained from the Neurological Foundation of New Zealand Human Brain Bank at the University of Auckland — from Alzheimer’s patients and healthy individuals used as controls.
The levels of gingipains in neurons and astrocytes — star-shaped cells that provide support to other cells of the nervous system — in the hippocampus were significantly higher in Alzheimer’s patients than in controls.
Gingipains were found together with tau tangles — aggregates of tau protein, a primary marker of Alzheimer’s— in the brain of Alzheimer’s patients. Using lab-cultured cells, researchers showed that gingipains break down tau protein, the fragmented version of which contributes to the formation of Alzheimer’s-related toxic insoluble tau.
Scientists also found P. gingivalis DNA in Alzheimer patients’ brains and in the cerebrospinal fluid (CSF) — the liquid that surrounds the brain and spinal cord — of living patients diagnosed with probable Alzheimer’s disease, indicating that the measurement of P. gingivalis’ DNA in CSF could potentially be a differential diagnostic marker.
To understand if gingipains were toxic to neurons, the team exposed neuroblastoma — a type of nerve cell cancer — cells to molecular parts (RgpB or Kgp) of gingipains. After 24 hours of combined application of both RgpB and Kgp, cell aggregation was significantly increased.
“On the basis of the cytotoxic activity of gingipains from P. gingivalis, their presence in [Alzheimer’s disease] brain, and their critical role in bacterial survival and virulence, we developed a library of potent and selective reversible and irreversible small-molecule gingipain inhibitors,” the researchers wrote.
Lab-cultured cells infected with a strain of P. gingivalis — which if not treated, had a death rate of up to 50% — were treated with molecular inhibitors of gingipains called COR286 and COR271. Depending on their concentration, these inhibitors effectively blocked P. gingivalis-induced cell death.
The team then tested if gingipains were neurotoxic in mice. Animals were given a single administration of gingipain inhibitors: COR271 directly into the stomach or COR286 by under-the-skin injection, or both.
One and a half hours later, Kgp and RgpB or a saline solution (control) were injected into the hippocampus of treated animals. A week after that, mice injected with gingipains had a significantly greater number of degenerating neurons than saline-injected animals, but pre-treatment with a combination of gingipain inhibitors COR286 and COR271 blocked some of the neurodegenerative process.
Kgp inhibitor COR271 significantly reduced the bacterial load in infected animals’ brains five weeks after the start of treatment. RgpB inhibitor COR286 could also effectively reduce the brain bacterial load, although it did so only at 10 weeks after treatment start.
“Combinations of COR271 with moxifloxacin [broad-spectrum antibiotic] or COR286 did not improve efficacy over COR271 alone,” the researchers said.
P. gingivalis-infected mice also showed significantly increased levels of beta-amyloid 1-42 — the predominant form of beta-amyloid found in the brains of Alzheimer’s patients. This beta-amyloid variant also had antibacterial effects against Porphyomonas gingivalis.
In addition to the previous inhibitors, the team developed COR388, a gingipain inhibitor biologically similar to COR271 but with a superior pharmacological profile. They showed that P. gingivalis developed rapid resistance to moxifloxacin, a broad-spectrum antibiotic, but not to the Kgp inhibitor COR388.
COR388’s safety and tolerability is being studied in a Phase 1 clinical trial (NCT03331900).
“Maintaining good dental health is an important part of a healthy lifestyle, and while we don’t yet fully know the extent to which it can affect our dementia risk, the presence of a single type of bacteria is extremely unlikely to be the only cause of the condition,” David Reynolds, PhD, chief scientific officer at Alzheimer’s Research UK, said in a press release.
“Drugs targeting the bacteria’s toxic proteins have so far only shown benefit in mice, yet with no new dementia treatments in over 15 years it’s important that we test as many approaches as possible to tackle diseases like Alzheimer’s. It’s important we carefully assess all new potential treatments, and this drug is currently in an early phase clinical trial to establish if it is safe for people. We will have to see the outcome of this ongoing trial before we know more about its potential as a treatment for Alzheimer’s,” he added.
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