Fiver wrote:Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors
Last, we have shown that broad-spectrum antibiotics do not protect against P. gingivalis–induced cell death in vitro, whereas gingipain inhibitors do. We also demonstrated in vivo that an orally administered Kgp inhibitor is more effective than a high-dose subcutaneous broad-spectrum antibiotic in clearing P. gingivalis from the brain. ... In contrast, we report here that small-molecule inhibition of the cysteine protease Kgp reduced not only disease pathology in mouse brain but also P. gingivalis bacterial load. ... We have demonstrated that P. gingivalis develops rapid resistance to a broad-spectrum antibiotic, moxifloxacin, but not to the Kgp inhibitor COR388. ...
In conclusion, we have designed an orally bioavailable, brain-penetrant Kgp inhibitor currently being tested in human clinical studies for AD. The present data indicate that treatment with a potent and selective Kgp inhibitor will reduce P. gingivalis infection in the brain and slow or prevent further neurodegeneration and accumulation of pathology in AD patients. ...
Here, we have not addressed how P. gingivalis infection might relate to apolipoprotein E4 (APOE4), the greatest genetic risk factor for sporadic AD (77). Studies in mice deficient in APOE proteins demonstrated an impaired innate immune response to the bacterial pathogen Listeria monocytogenes (78), implicating APOE in normal innate immune function in vivo. It was recently reported that human APOE is a target of gingipain proteolysis, and the authors suggested that this mechanism could generate neurotoxic APOE fragments in the AD brain (79). We propose that APOE4 may be more susceptible to gingipain cleavage than APOE3 or APOE2 due to the presence of more arginine residues, resulting in decreased innate immune function and the generation of neurotoxic fragments (80). The distinct role of APOE in relation to P. gingivalis infection and targeting by gingipains remains a focus of future studies.
The mean gingival index was 0.91 and the plaque index was 1.19 at baseline. In comparison to the baseline values both the gingival and the plaque indices substantially reduced during the period of assessment. There was a steady decline in both the plaque index and the gingival index values from day 7. The average gingival index score on day 30 was down to 0.401 and the plaque index score was 0.385
I may have a naive question here regarding this article and a recent thread on the breakdown of the blood brain barrier. Isn't the BBB supposed to keep bacteria like this, as well as other pathogens (HSV?), out of the functional brain regions? How do these pathogens get in if the BBB is healthy and intact?
J11 wrote:Oh, might also need to be careful around man's best friend.
"P. gulae is a natural inhabitant of the oral cavity of companion animals such as dogs, and a recent study demonstrated that dogs can transmit P. gulae to the oral cavity of their owners (62). Research is underway to determine whether P. gulae may be contributing to the gingipain load in AD brains."
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