Potential Bidirectional Relationship Between Periodontitis and Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population, representing a global public health priority. Despite a large improvement in understanding the pathogenesis of AD, the etiology of this disorder remains still unclear, and no current treatment is able to prevent, slow, or stop its progression. Thus, there is a keen interest in the identification and modification of the risk factors and novel molecular mechanisms associated with the development and progression of AD. In this context, it is worth noting that several findings support the existence of a direct link between neuronal and non-neuronal inflammation/infection and AD progression. Importantly, recent studies are now supporting the existence of a direct relationship between periodontitis, a chronic inflammatory oral disease, and AD. The mechanisms underlying the association remain to be fully elucidated, however, it is generally accepted, although not confirmed, that oral pathogens can penetrate the bloodstream, inducing a low-grade systemic inflammation that negatively affects brain function. Indeed, a recent report demonstrated that oral pathogens and their toxic proteins infect the brain of AD patients. For instance, when AD progresses from the early to the more advanced stages, patients could no longer be able to adequately adhere to proper oral hygiene practices, thus leading to oral dysbiosis that, in turn, fuels infection, such as periodontitis. Therefore, in this review, we will provide an update on the emerging (preclinical and clinical) evidence that supports the relationship existing between periodontitis and AD. More in detail, we will discuss data attesting that periodontitis and AD share common risk factors and a similar hyper-inflammatory phenotype.

Keywords: Alzheimer’s disease; dementia; dysbiosis; neurodegeneration; periodontitis.

FIGURE 1

Diagram of the non-amyloidogenic and the amyloidogenic proteolytic pathway for the amyloid precursor protein (APP). Non-amyloidogenic pathway: α-secretase cleaves the transmembrane protein APP to release the soluble APP fragment, sAPPα. The APP C-terminal fragment is then processed by γ-secretase to release an intracellular domain (AICD) and the P3 fragment. Amyloidogenic pathway: β-secretase processes APP to generate the soluble fragment, sAPP-β, then cleaved γ-secretase Aβ peptides (AβPs), and the AICD.

FIGURE 2

Scheme of the proposed mechanism linking periodontitis to Alzheimer’s disease: (1) Oral dysbiosis of the dental plaque leads to proliferation, tissue invasion, and then dissemination into the bloodstream of oral pathogens. (2) Next, the oral pathogens and their toxic molecules, such as lipopolysaccharide (LPS), bind to microglia via Toll-like receptors 2/4 (TLR2/4), inducing the release of cytokines (3) and inflammatory mediators that, in turn, lead to APP processing from neuronal cells. (3–4) Subsequently, the activation of β- and γ-secretase leads to an increased secretion of Aβ peptides (AβPs), in particular Aβ42 monomers and sAPPβ, outside of the cells and AICD intracellularly. (4) AβPs form oligomers, protofibrils, or fibrils and then amyloid plaques that are recognized by TREM2 receptors on the microglia plasma membrane, thus triggering an inflammatory response, which again stimulates AβP production. Dysfunctional neurons present also increased tau phosphorylation (p-tau) with the formation of neurofibrillary tangles (p-tau tangles). All these processes induce neuronal degeneration.