For decades, the predominant hypotheses for the cause of Alzheimer’s disease have centred around the accumulation of amyloid and tau protein in the brain. Research into Alzheimer’s treatments have focused on the amyloid hypothesis. This theory postulates that a failure to degrade amyloid β peptides, and consequentially the formation of amyloid fibrils and their aggregation into plaques, is responsible for the symptoms of neurodegeneration observed in Alzheimer’s disease (Kametani & Hasegawa, 2018).
However, as a result of findings demonstrating the presence of amyloid plaques and tau tangles in the brains of patients who do not exhibit signs of dementia, as well as the 99% failure rate of drug development for Alzheimer’s, further exploration of other approaches to the disease is currently underway (Kametani & Hasegawa, 2018; Mackenzie, 2019).
One such approach revolves around Porphyromonas gingivalis, the main bacterium implicated in periodontitis, an advanced stage of gum disease. Previous findings have shown an association between gum disease and the risk of Alzheimer’s. In addition, recent research has indicated that amyloid β peptides perform an antimicrobial role in the body. A proposed mechanism for this action involves amyloid β peptides inhibiting adhesion of microbes to host cells, and subsequently mediating agglutination and entrapment of microbial cells within a network (Kumar et al., 2016; Mackenzie, 2019).
It has previously been speculated that the cognitive impairment caused by Alzheimer’s is responsible for poor oral hygiene practice, thus raising the patient’s risk of developing gum disease. However, the identification of amyloid β peptides as antimicrobial has led to development of the theory that periodontitis can lead to Alzheimer’s disease, and is not necessarily an outcome of the condition. Signs of neuroinflammation indicative of infection have also been observed in patients with Alzheimer’s, including activation of microglia, the complement system, and inflammasomes (cytosolic multiprotein complexes which work to induce pyroptosis and secrete inflammatory cytokines). In mice, oral infection with P. gingivalis has been shown to give rise to brain infection and increased levels of amyloid β peptides. These findings, in combination with the discovery that Alzheimer’s patients with active chronic periodontitis appear to experience greater decline in cognitive abilities (compared to Alzheimer’s patients without active chronic periodontitis, as measured over a period of 6 months), have inspired further research into the potential mechanisms by which P. gingivalis may enter the brain and lead to neurodegeneration (Dominy et al., 2019; Mackenzie, 2019).
Following oral infection, damage to the gums may enable P. gingivalis to enter the blood stream, travelling to the blood-brain barrier. This structure acts as an interface between the central nervous system and the periphery, regulating the transfer of substances between these regions. P. gingivalis may bypass this defence system by directly infecting monocytes, which are then recruited to the brain, by infecting endothelial cells at the blood-brain barrier, or by travelling across cranial nerves into the brain.
After entering the brain, one potential mechanism by which P. gingivalis may cause neuronal damage relates to the secretion of gingipains. These factors are cysteine proteases, and are involved in inactivation of the host’s defence systems, digestion of host proteins to obtain nutrients for growth, and tissue damage. Significantly higher levels of gingipains have been observed in patient’s brains, as compared to control brains. Treating mice with gingipains has been shown to raise the number of degenerating neurons, as compared to mice injected with saline. However, this neurodegeneration could be prevented by use of gingipain inhibitors.
The gingipains may contribute to neurodegeneration by cleaving APOE proteins. This proteolysis may produce neurotoxic fragments. Certain fragments, such as one formed from APOE4, are capable of increasing production of intracellular reactive oxygen species. This can lead to oxidative stress, a feature commonly observed in Alzheimer’s disease (Dominy et al., 2019; Mackenzie, 2019).
While further study into P. gingivalis and the potential mechanisms by which it may impact neurodegeneration in humans is required, recent findings on the effect of gingipains provide hope in the search for a treatment for Alzheimer’s. A medication developed by Cortexyme which targets gingipains is currently undergoing study, with final analysis of a phase 2/3 trial expected next year.
Dominy, S.S., Lynch, C., Ermini, F., Benedyk, M., Marczyk, A., Konradi, A., Nguyen, M., Haditsch, U., Raha, D., Griffin, C. and Holsinger, L.J. (2019) Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Science Advances. 5, (1). Available from: doi:10.1126/sciadv.aau3333
Kametani, F. & Hasegawa, M. (2018) Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer’s Disease. Frontiers in Neuroscience. 12, (25). Available from: doi:10.3389/fnins.2018.00025
Kumar, D.K.V., Choi, S.H., Washicosky, K.J., Eimer, W.A., Tucker, S., Ghofrani, J., Lefkowitz, A., McColl, G., Goldstein, L.E., Tanzi, R.E. and Moir, R.D. (2016) Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Science Translational Medicine. 8, (340). Available from: doi: 10.1126/scitranslmed.aaf1059
Mackenzie, D. (2019) We may finally know what causes Alzheimer’s – and how to stop it. New Scientist, 23 January. Available at: https://www.newscientist.com/article/2191814-we-may-finally-know-what-causes-alzheimers-and-how-to-stop-it/ (Accessed: 25 August 2020)