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Gum disease bacteria linked to alzheimer's

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  • Gum disease bacteria linked to alzheimer's

    http://advances.sciencemag.org/content/5/1/eaau3333

    Abstract

    Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer’s disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer’s patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalisinfection in mice resulted in brain colonization and increased production of Aβ1–42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ1–42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer’s disease.
    "Whenever you find yourself on the side of the majority, it is time to pause and reflect." –Mark Twain

  • #2
    I pulled the paper (its free to download); they're already in human trials! I don't know how "locked-in" their data is, and wont until Phase 3 results are published (in a few years), but this could be really huge. Particularly (from my perspective) because they're going after a virulence target rather than a viability target (aka, they're targeting a protein the bacteria use to infect hosts, rather than one the bacteria need to live) -- I work on virulence targets, and they're pretty underexplored as a antiinfective strategy (aka: no one has done it in humans ever). There are a couple of potential advantages:

    1. specificity; because virulence mechanisms aren't essential for survival, there is a huge amount of variability, particularly among species -- there isn't as much selection pressure to minimize mutation. Additionally, many virulence pathways simply don't exist in symbiotic microbiomes. Why is this important? Many diseases (notably: C. diff) occur in response to major disruption of microbiomes -- almost all cases of C. diff occur in the direct aftermath of potent broad-spectrum antibiotic use. Additionally, its becoming more and more evident that other pathogens (such as P. aeruginosa) cause infections when specific microbiome bacteria that occupy a similar "environmental niche" get wiped out -- at Northwestern University Hospital, they saw a dramatic reduction in P. aeruginosa pneumonia cases in their ICU when they started restricting vancomycin use to treat S. aureus infections to only those which explicitly demonstrated high levels of sensistivity to vancomycin; P. aeruginosa pneumonia kills roughly 50% of everyone who gets it.

    2. Resistance; there is something called the "common good hypothesis" regarding virulence factors, where only a subset of the bacterial population need to generate a functional virulence factor to result in the net virulence effect -- at its core, this is well-established. What's less certain is how this would impact resistance development -- when a resistant mutant is formed, there wouldn't be direct selection pressure that could cause it to take over the population the way you would see with resistance to a bactericidal agent -- as such, they wouldn't be as likely to be passed on from patient to patient, and the emergence of widespread resistance would be dramatically delayed.

    Neither of these two advantages are well established clinically, and any new drugs that fit this model would dramatically improve our understanding of such systems. If these two hypotheses were borne out clinically, it would drive resources towards antivirulence factors, potentially unleashing a "next generation" of antiinfectives that could be as dramatically better for patients as modern chemotherapies are compared to methotrexate and other historical "kill the cancer faster than the patient" drugs.
    Porphyromonas gingivalis , the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer’s disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer’s patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalis infection in mice resulted in brain colonization and increased production of Aβ1–42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ1–42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer’s disease.
    They speak in bulletpointese leftist nutjob drivel. It doesn't matter. Nothing is as great a motivator as the chance to truly be free.
    -Mr. Raceboy

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    • #3
      That's really good information. I've never heard of virulence factors, so that's something I'll look out for.

      Jared (administers vancomycin fairly regularly)
      "Whenever you find yourself on the side of the majority, it is time to pause and reflect." –Mark Twain

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