Project Summary/Abstract
Albeit periodontal disease is a local chronic infectious inflammatory process affecting tissues supporting teeth,
it can also have systemic consequences. Along these lines are reports that Alzheimer’s disease (AD) is
epidemiologically associated with periodontal disease. Yet, the mechanisms underlying this association are
not delineated. Our preliminary studies provide new evidence that a keystone periodontal pathogen
Porphyromonas gingivalis (Pg) could enter the brain and exacerbate amyloid-b (Ab) accumulation,
neuroinflammation, microglia activation, synapse loss, and cognitive and behavioral impairments in AD mice
upon oral gavage infection. Microglia are the primary innate immune cells in the brain, and microglial
activation is an invariable feature of AD pathology. The complement system also represents a major part of
innate immunity, and microglia have been identified as the dominant source of C1q, the initiation factor of the
classical complement pathway, in the brain. The objective of this application is to understand the importance
of periodontitis in regulating microglial in AD, and the role of complement component C1q in microglial
activation and AD progression. Based on the literature and our preliminary results, we hypothesize that
periodontal infection and inflammation not only increase the severity of AD, but also increase the risk of AD,
via potentiating Ab-primed microglial activation and sensitizing microglia for a heightened inflammatory
response to subsequent pathogenic stimuli. In addition, periodontitis-associated persistent C1q activation is
critical for microglial priming and activation, and the increased neurodegeneration in AD. We will test our
hypothesis by pursuing two specific aims. Aim 1 will determine how periodontitis regulates microglial
activation in AD using three different models of periodontitis. Aim 2 will determine the role of complement
component C1q in microglial activation and AD development following Pg infection. Our proposed studies
will provide novel and significant insights into the association between periodontal infection and AD.
Understanding how a prevalent chronic infection like periodontitis modulates complement and microglial
activation will advance our understanding of the mysterious etiology of AD. The knowledge obtained from
these studies will provide a basis for targeting microbial etiology and periodontal therapy to ameliorate the
clinical manifestations of AD and lower AD prevalence.