Investigating the impacts of periodontitis on neuroinflammation, neuropathology, and neurodeneration of Alzheimer's disease

Abstract

Systemic activation of the immune system can be extremely harmful to the central nervous system (CNS). Periodontitis, a chronic disease of the oral cavity, is a source of systemic inflammation caused by the imbalance in the interaction between the host immune response and the oral microbiome at the gingival mucosa barrier interface. Consequently, neuroinflammation can occur which can accelerate the age-dependent deterioration of neuronal functions or exacerbate pre-existing neurological conditions such as Alzheimer’s disease (AD). As periodontitis is a major oral health problem in the elderly and AD patients, systemic inflammation resulting from it would thus contribute to the onset and progression of AD. One shared risk factor between periodontitis and AD is age. In the first part of the study, periodontal inflammation was found to contribute to the loss of periodontal bone levels during the aging process. In the aging brain, the increased neuroinflammatory state contributed to changes in behavior and cognitive functions. With increasing age, the progressive increase in the body’s pro-inflammatory status favors the state of vulnerability to periodontitis and AD. The increased pro-inflammatory status in the periodontium and the brain along with the progressive deterioration of cognitive functions led me to further investigate whether periodontitis-induced periodontal inflammation would accelerate the normal aging process and modulate the risk of AD in normal non-transgenic (nTg) mice. Systemic inflammation induced by experimental periodontitis was found to modulate neuroimmune responses, tau solubility and phosphorylation, as well as behavior and cognition, contributing to the risk of AD. Given that neuroinflammation is one of the core pathologies of AD, periodontitis may thus amplify the neuroimmune response and influence AD progression. By employing a triple transgenic mouse model of AD (3×Tg-AD), experimental periodontitis potentiated pathological features and exacerbated cognitive impairment in AD mice. As inflammatory responses resulting from periodontitis were found to associate with AD progression, I then hypothesized that managing periodontitis using a broad-spectrum tetracycline antibiotic, doxycycline, would ameliorate the aggravated neuropathological features and cognitive dysfunctions caused by experimental periodontitis in 3×Tg-AD mice. Here, I found that doxycycline treatment significantly reduced total oral bacterial load, abolished periodontitis-induced periodontal inflammation, and concomitantly reduced pro-inflammatory cytokine levels in the periphery and the CNS. The decreases in pro-inflammatory cytokines observed were associated with cognitive improvement, signifying the potential role of peripheral inflammatory cytokines on AD. Finally, I sought to delineate the roles of pro-inflammatory cytokines in the pathogenesis of periodontitis and AD. Interleukin (IL)-1β and tumor necrosis factor (TNF)-α are two of the most important and earliest cytokines upregulated upon periodontal infection. Injections of these two cytokines into the mandibular buccal vestibule mimicked characteristic features of periodontitis, induced systemic inflammation, and increased neuroimmune responses. It also modulated the behavior and cognition of nTg mice. Following systemic challenge, locus coeruleus (LC) neuronal damage and inflammation could also be observed, implicating the potential involvement of the LC-norepinephrine pathway in linking periodontitis to AD. This study provides convincing evidence that systemic inflammation serves as a connecting link between periodontitis and AD.