Towards Targeting the Toxins of Oral Bacteria in the Alzheimer's Brain

There is a clear association between poor dental hygiene and incidence of Alzheimer's disease, but is this a direct mechanism, or more a reflection of other health practices and lifestyle choices made by the sort of person who has poor dental hygiene? The direct mechanisms are thought to be (a) chronic inflammation, in the sense that gum disease allows bacteria and bacterial toxins access to the bloodstream, and this will rouse the immune system or (b) some other effect arising from the impact of bacterial toxins on critical cells in the brain.

That these direct mechanisms exist is clear: the evidence here adds to numerous past studies that show the gingipains secreted by Porphyromonas gingivalis, the most important bacterial species in gum disease, can be a real problem. But what is the size of the effect in practice, in humans rather than in animal models set up specifically to demonstrate the mechanisms in question? Recent epidemiological work suggests it is only a small contribution to the risk of dementia such as Alzheimer's disease. The best way forward is probably exactly that demonstrated here, which is to say find a way to fix the problem, then test that fix and observe the results.

Alzheimer's disease (AD) patients exhibit neuroinflammation consistent with infection. Infectious agents have been found in the brain and postulated to be involved with AD, but robust evidence of causation has not been established. The recent characterization of amyloid-β (Aβ) as an antimicrobial peptide has renewed interest in identifying a possible infectious cause of AD. Chronic periodontitis (CP) and infection with Porphyromonas gingivalis - a keystone pathogen in the development of CP - have been identified as significant risk factors for developing Aβ plaques, dementia, and AD.

A prospective observational study of AD patients with active CP reported a notable decline in cognition over a 6-month period compared to AD patients without active CP, raising questions about possible mechanisms underlying these findings. P. gingivalis lipopolysaccharide has been detected in human AD brains, promoting the hypothesis that P. gingivalis infection of the brain plays a role in AD pathogenesis.

P. gingivalis is an asaccharolytic Gram-negative anaerobic bacterium that produces major virulence factors known as gingipains. We hypothesized that P. gingivalis infection acts in AD pathogenesis through the secretion of gingipains to promote neuronal damage. We found that gingipain immunoreactivity in AD brains was significantly greater than in brains of non-AD control individuals. In addition, we identified P. gingivalis DNA in AD brains and the cerebrospinal fluid (CSF) of living subjects diagnosed with probable AD, suggesting that CSF P. gingivalis DNA may serve as a differential diagnostic marker. We developed and tested potent, selective, brain-penetrant, small-molecule gingipain inhibitors in vivo. Our results indicate that small-molecule inhibition of gingipains has the potential to be disease modifying in AD.



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