Ligature-induced periodontitis in a transgenic mouse model of Alzheimer's disease dysregulates neuroinflammation, exacerbates cognitive impairment, and accelerates amyloid pathology.

A growing body of literature has identified periodontal disease among the modifiable risk factors for Alzheimer's disease (AD), but the mechanisms underlying this relationship is unknown. This study investigated this relationship using a ligature-induced preclinical periodontitis (Pd) model in non-transgenic (non-Tg) and 3xTg-AD mice. We found that ligature placement caused significant alveolar bone loss, with 3xTg-AD mice exhibiting exacerbated bone loss, suggesting AD-related genetic risk may amplify disease progression. Pd induced robust local inflammatory gene expression in both genotypes, but 3xTg-AD mice indicated a dysregulated immune response. Cognitive deficits were observed only in Pd-afflicted 3xTg-AD mice, specifically in hippocampus-mediated spatial memory and perirhinal cortex-mediated object recognition memory, while non-Tg mice remained unaffected. Neuroinflammatory responses varied by brain region, with the hippocampus and prefrontal cortex (PFC) showing the most pronounced changes. In these regions, 3xTg-AD mice exhibited significantly altered cytokine gene expression compared to non-Tg mice, particularly at later time points. Synaptic markers revealed vulnerabilities in 3xTg-AD mice, including reduced baseline Syp expression and dysregulated Synpo post-ligature. Pd transiently reduced glutamate receptor gene expression in both genotypes, with non-Tg mice showing persistent changes, potentially linked to preserved memory. Pd also accelerated amyloid-β (Aβ) deposition and sustained neurodegeneration in 3xTg-AD mice. Overall, this study shows that combining Pd and AD-related genetic risk exacerbates inflammation, cognitive impairment, synaptic dysfunction, Aβ pathology, and neurodegeneration. Neither insult alone was sufficient to produce these effects, highlighting the synergistic impact. These findings emphasize the need to explore anti-inflammatory interventions and downstream mechanisms to mitigate the confluence of these diseases.