Porphyromonas gingivalis Promotes Lipid Droplet–Mediated Microglial Dysfunction

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Abstract
Growing evidence supports a strong association between periodontitis and Alzheimer’s disease (AD), yet the mechanisms linking these conditions remain poorly defined. In neurodegenerative disorders, including AD, microglia are often characterized by increased accumulation of lipid droplets (LD), heightened activation, and impaired function. In this study, we examined whether Porphyromonas gingivalis ( Pg ), a keystone periodontal pathogen, promotes LD accumulation in microglia and disrupts their function. We found that infection with Pg (ATCC 33277) induces robust LD accumulation in BV2 microglial cells and in microglia from Pg -infected App knock-in mice. This Pg -driven LD buildup was closely associated with elevated reactive oxygen species (ROS) production, impaired phagocytic ability, and altered activation. Notably, pharmacologic inhibition of LD with a long-chain fatty acyl-CoA synthetase inhibitor effectively reversed Pg -induced LD accumulation, mitigated ROS production, and restored phagocytic function, thus underscoring the critical role of lipid metabolism in regulating microglial function. These findings support a model in which, in the context of periodontitis, systemic dissemination of periodontal pathogens and inflammatory mediators promotes LD accumulation in microglia, and this metabolic alteration exacerbates microglia dysfunction via a self-reinforcing cycle of excessive oxidative stress and impaired phagocytosis, potentially accelerating AD progression.
Funding Information
  • U.S. Department of Veterans Affairs (BX006231)
  • National Institutes of Health (P30AI27667)
  • National Institutes of Health (P30AR048311)
  • National Institute of Aging (R01 AG078708)
  • UAB Global Center for Craniofacial, Oral and Dental Disorders (GC-CODED)
  • National Institute of Dental and Craniofacial Research (R01 DE026465)
  • NIDCR Dental Academic Research Training grant (R90 DE023056)

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