Age-dependent changes in the periodontium and the neuropathological features of 3xTg mice as well as the impact of periodontitis on Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is the most common form of dementia characterized by the presence of amyloid plaque and neurofibrillary tangles. Over the years, neuroinflammation has emerged to be the third core pathology of AD that plays a central role in the disease pathogenesis. This response is characterized by activation of microglia and astrocytes. Emerging epidemiological studies have shown that peripheral immune activation can lead to neuroimmune responses through activation of glial cells. One of the common sources of chronic systemic inflammation is periodontitis, which is an advanced form of periodontal disease induced by oral pathogenic bacteria, leading to alveolar bone loss and ultimately tooth loss. As periodontitis is the major oral health problem in both elderly and AD patients, it suggests that it may intensify the neuroimmune responses in AD and exacerbate the disease conditions. While aging is the major risk factor for AD, other studies also confirmed that occurrence and severity of periodontal destruction increases with age. One of the reasons is that advancing age leads to dysregulation of the immune system. By employing Micro-CT (micro-computed tomography) scan, our data revealed that in comparison to young 3xTg mice, old mice displayed significantly (p < 0.05) increased periodontal bone loss. In addition, as the severity of AD pathology increases with age in 3xTg mice, cognitive functions of these mice were also examined. Our results showed that aged mice displayed a worse cognitive performance. Increased neuropathology in the brains of aged 3xTg was also observed. Coincidently, the increase in periodontal bone loss and worsened cognitive functions in aged 3xTg AD mice led us to question whether periodontitis would induce and/or exacerbate neuroimmune responses and cognitive impairments. To address the question, female mice at 6 months old were injected with heat-killed P. gingivalis bacteria into their buccal mucosa three times per week every other week for a total of 6 weeks to establish periodontitis. After infection, cognitive functions of mice were assessed and some had undergone MicroPET scan, which is a unique technology that measures the brain glucose metabolism. Also, significant increase of the pro-inflammatory cytokines IL-1β and IL-6 were found in the frontal cortex, MCP-1 in the hypothalamus and IL-1β in the hippocampus of mice after periodontal infection. Together, these findings prove the relevance of the current periodontitis model to further examine neuroimmune responses and AD pathologies in the brains of 3xTg mice.