J Alzheimers Dis. 2013 Jan 1;36(4):665-77

Determining the presence of periodontopathic virulence factors in short-term post-mortem Alzheimer’s disease brain tissue

Poole S1, Singhrao SK1*, Kesavalu L2, Curtis MA3, Crean S1

*1Oral & Dental Sciences Research Group, University of Central Lancashire,

2Department of Periodontology and Oral Biology, College of Dentistry, University of Florida,

3Blizard Institute of cell & Molecular Science, Queen Mary University of London, UK


The aim of this study was to establish a link between periodontal disease and Alzheimer’s disease (AD) with a view to identifying the major periodontal disease bacteria (Treponema denticola, Tannerella forsythia, and Porphyromonas gingivalis) and/or bacterial components in brain tissue from 12 h postmortem delay. Our request matched 10 AD cases for tissue from Brains for Dementia Research alongside 10 non-AD age-related controls with similar or greater postmortem interval. We exposed SVGp12, an astrocyte cell line, to culture supernatant containing lipopolysaccharide (LPS) from the putative periodontal bacteria P. gingivalis. The challenged SVGp12 cells and cryosections from AD and control brains were immunolabeled and immunoblotted using a battery of antibodies including the anti-P. gingivalis-specific monoclonal antibody. Immunofluorescence labelling demonstrated the SVGp12 cell line was able to adsorb LPS from culture supernatant on its surface membrane; similar labelling was observed in four out of 10 AD cases. Immunoblotting demonstrated bands corresponding to LPS from P. gingivalis in the SVGp12 cell lysate and in the same four AD brain specimens which were positive when screened by immunofluorescence. All controls remained negative throughout while the same four cases were consistently positive for P. gingivalis LPS (p = 0.029). This study confirms that LPS from periodontal bacteria can access the AD brain during life as labelling in the corresponding controls, with equivalent/longer postmortem interval, was absent. Demonstration of a known chronic oral-pathogen-related virulence factor reaching the human brains suggests an inflammatory role in the existing AD pathology.

PMID: 23666172



In 1891, Willoughby D. Miller coined the words “focal infection” in his publication in the Dental Cosmos journal. He implied that a focal infection involved the microbes and their virulence factors from the “foci” of oral microbial infections affecting teeth, mobilise from the mouth and may be responsible for causing infections elsewhere in the body (Miller, 1891). Almost a decade later, an English physician, William Hunter (Hunter, 1900), a strong supporter of the concept observed that the origins of caries, pulpal necrosis and periodontitis were all microbial and proposed they affected the health of remote body organs and induce systemic diseases. This interesting phenomenon has become accepted as the William Hunter’s “focal infection theory” (Hunter, 1900). The contributory factors, as he believed was, surgical intervention during diseased tooth restoration in which oral pathogens were being trapped below the gingival surfaces and entered the vascular channels via “oral sepsis”. However, it is now clear that the infectious agents that drive periodontal disease possess the molecular armoury to destroy tooth supporting tissues via initiation of the host’s own immune responses (Haffajee et al., 1988) thereby having direct access to the systemic circulation to reach distant organ sites. The brain is particularly susceptible to oral infections as lies close to the mouth where the olfactory and the trigeminal nerves pathways cross connections to the anterior (frontal lobe) and the posterior (pons) sections (Danielyan et al., 2009; Johnson et al., 2010) and via the blood supply of the body (Figure 1). The nerve pathways together with the systemic channels (at circumventricular organ sites) are exploited by periodontal pathogens as a means of bypassing the blood-brain barrier for direct entry into the central nervous system (Riviere et al., 2002). By finding associations of periodontal pathogens with Alzheimer’s disease, the Poole et al., (2013) and the Riviere et al., (2002) studies go some way towards supporting the “focal infection” hypothesis. However, further studies are needed to demonstrate the causal association between the two diseases.Sim K. Singhrao-jpgFigure 1: Schematic diagram showing possible routes of oral pathogen entry into the brain. Live motile bacteria in the oral cavity can gain direct access to the brain via the, trigeminal and the olfactory nerve pathways. Recurrent bacteraemia and bacterial components from the systemic circulation can also gain access to the brain, within the damaged systemic channels (blood vessels – BV) merging again at the circumventricular organ sites. If organisms are in their live state they can cross the ependymal epithelial cell layer lining the ventricle wall for entry into the brain parenchyma.



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Dr S. K. Singhrao,

Senior Research Fellow,

Oral & Dental Sciences Research Group,

School of medicine and Dentistry,

University of Central Lancashire,

Preston PR1 2HE

E-mail: SKSinghrao@uclan.ac.uk

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