Laboratory studies may provide new therapeutic target for Alzheimer’s disease
The National Institute on Aging, part of the National Institutes of Health, has awarded NYU Dentistry a $3.1 million grant to study the nexus of periodontitis and Alzheimer’s disease.
Periodontitis is chronic inflammation of the gums that can lead to inflammation throughout the body and brain. A growing number of studies suggests that patients with periodontitis may be at higher risk of developing Alzheimer’s disease, a degenerative brain disorder that affects more than 6 million older adults in the U.S. and is the sixth leading cause of death.
“Alzheimer’s disease is a growing public health crisis, but we still have limited knowledge about how the disease develops. We’re trying to understand if and how periodontitis promotes the pathogenesis of Alzheimer’s, which could offer clues on how to treat or prevent the disease,” said Xin Li, PhD, professor of molecular pathobiology at NYU Dentistry and the principal investigator on the new grant.
Preliminary data from Li and her colleagues shows that a metabolic byproduct called succinate is significantly increased in the cerebrospinal fluid of mice with periodontitis. Their research also found that microglial cells-immune cells in the central nervous system that play a role in infection and inflammation and are crucial for the homeostasis within the brain-express the succinate receptor (SUCNR1). When mice with periodontitis were genetically altered to inactivate (or “knock out”) SUCNR1, their increases of pro-inflammatory cytokines and microglial activation were significantly reduced.
The researchers hypothesize that elevated succinate in periodontitis induces neurodegeneration directly by activating SUCNR1 in microglial cells, and indirectly through systemic inflammation and creating an imbalance in the oral microbiome. They plan to conduct a series of studies in cells and mice to examine how SUCNR1 activation in microglial cells modulates neuroinflammation. They will then test whether blocking SUCNR1 in mice with periodontitis alleviates neuroinflammation, cognitive impairment, and periodontal bone loss.
“These studies are designed to identify the mechanism by which periodontitis increases succinate in cerebrospinal fluid and activates the succinate receptor in microglial cells to induce neuroinflammation and neurodegeneration,” said Li. “If we then find that targeting the succinate receptor reduces neuroinflammation and cognitive impairment in animal models, this may provide a potential new therapeutic target for Alzheimer’s disease.”
The five-year grant (R01AG080696) began on January 1.