Serotype b of Aggregatibacter actinomycetemcomitans triggers pro-inflammatory responses and amyloid beta secretion in hippocampal cells: a novel link between periodontitis and Alzheimer´s disease?

Abstract

Introduction: Previous reports have proposed that Periodontal disease (PDis) predisposes to Alzheimer's disease (AD), both highly prevalent pathologies among the elderly. The bacteria Aggregatibacter actinomycetemcomitans (Aa), associated with the most aggressive forms of PDis, are classified in different serotypes with distinct virulence according to the antigenicity of their lipopolysaccharide (LPS). Methods: Here, we determined the effects of purified LPS, from serotypes a, b or c of Aa, on primary cultures of microglia or mixed hippocampal cells. Results: We found that both culture types exhibited higher levels of inflammatory cytokines (IL-1β, IL-6 and TNFα) when treated with serotype b-LPS, compared with controls, as quantified by qPCR and/or ELISA. Also, cultures treated with serotype a-LPS displayed increased mRNA levels of the modulatory cytokines IL-4 and IL-10. Mixed hippocampal cultures treated with serotype b-LPS exhibited severe neuronal morphological changes and displayed increased levels of secreted Aβ 1-42 peptide. These results indicate that LPS from different Aa serotypes triggers discriminatory immune responses, which differentially affect primary hippocampal cells. Conclusion: Altogether, our results show that treatment with serotype b-LPS triggers the secretion of proinflammatory cytokines by microglia, induces neurite shrinking, and increases the extracellular Aβ1-42 levels, all features strongly associated with the etiology of AD.

Potential Bidirectional Relationship Between Periodontitis and Alzheimer’s Disease

“…Furthermore, in a preclinical study from Ilievski and coworkers, it has been shown that in wild-type mice, P. gingivalis infection resulted in the neurodegeneration and formation of extracellular Aβ42 (Ilievski et al, 2018). Analogously, Díaz-Zúñiga et al (2019) demonstrated that in vitro LPS (from A. actinomycetemcomitans) increased neuroinflammation via the activation of microglia and the subsequent increase in pro-inflammatory cytokines and chemokines coupled to the accumulation of Aβ42. Importantly, LPS from P. gingivalis (LPS-PG) binds to glial cells (Poole et al, 2013), and in the AD brain, it is co-localized with Aβ plaques (Zhan et al, 2016;Zhao et al, 2017).…”

Alzheimer’s Disease-Like Pathology Triggered by Porphyromonas gingivalis in Wild Type Rats Is Serotype Dependent

“…Also, considering that periodontitis is a multibacterial disease, it would be interesting to contemplate the virulence effects of the other periodontal and gastrointestinal bacteria to which the human body is exposed to on a daily basis. In this regard, Aggregatibacter actinomycetemcomitans is recognized to be highly virulent; studies are in progress in our research group to determine whether this bacterium can also generate neuroinflammation in vivo, since we previously reported that serotype b of Aggregatibacter actinomycetemcomitans triggers pro-inflammatory responses and amyloid beta secretion in hippocampal cell cultures (37).…”

“…Interestingly, the possibility that the immune response induced in the brain might differ depending on the infecting capsular P. gingivalis serotype has never been exploited. Microglia are known to discriminate against different bacterial antigens, triggering the activation of divergent pathways according to the antigens recognized (35)(36)(37)(38). Thus, it is possible that some P. gingivalis strains might be more virulent than others in causing Alzheimer´s like-disease.…”

Cardiologists’ and Cardiovascular Surgeons’ Awareness, Opinions and Practice Behaviors Relating to the Association Between Periodontal Disease and Cardiovascular Disease

“…It is depended on the emerging data that suggests that periodontal disease provides the morbidity and mortality of individuals with systemic diseases such as premature birth, low birth weight, diabetes mellitus, Alzheimer's disease and cardiovascular problems like atherosclerosis and myocardial infarction. 8,9 Dentists are trained about the oral-systemic relationship during their professional education. 10,11 What is less clear is how medical providers are educated about oralsystemic research relating to periodontal diseases and systemic complications.…”