Porphyromonas gingivalis-Induced NETs Mediate Neuroinflammation via TLR4 Activation.

Area of Science:

• Neuroscience
• Immunology
• Periodontology

Background:

• Periodontitis, caused by pathogens like *Porphyromonas gingivalis*, is a risk factor for Alzheimer's disease (AD).
• Neutrophils in periodontitis release neutrophil extracellular traps (NETs), potentially linking oral health to neuroinflammation.

Purpose of the Study:

• To investigate the mechanism of *P. gingivalis*-induced NETs in periodontitis-associated neuroinflammation and cognitive impairment.
• To explore the role of Toll-like receptor 4 (TLR4) in these processes.

Main Methods:

• Established a murine periodontitis model using *P. gingivalis* and treated with a TLR4 inhibitor (tak242).
• Assessed alveolar bone resorption, neutrophil counts, NET formation, cognitive function, neuroinflammation markers, and amyloid precursor protein (APP) processing.
• Conducted in vitro experiments on neuron-glia cells to elucidate the functional mechanism.

Main Results:

• Periodontitis induced significant alveolar bone loss, increased neutrophils and NETs, and impaired cognitive abilities.
• Neuroinflammation, characterized by glial activation and elevated cytokines, along with altered APP processing, was observed.
• In vitro studies showed *P. gingivalis*-NETs induced M1 polarization and affected APP processing via TLR4/Myd88/NF-κB and GSK3β/Akt pathways.
• Tak242 treatment reversed these detrimental effects.

Conclusions:

• *P. gingivalis*-induced NETs play a critical role in the link between periodontitis, neuroinflammation, and cognitive impairment.
• The observed effects on the neuron-glia unit are mediated by TLR4 activation, suggesting it as a therapeutic target.