Periodontis bacteria linked to Alzheimer’s disease

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Fiver
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Periodontis bacteria linked to Alzheimer’s disease

Postby Fiver » Wed Jan 23, 2019 1:56 pm

Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors
http://advances.sciencemag.org/content/5/1/eaau3333

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.
Four relatives with AD. Concerned, but hopeful. Introverted, but will talk about science.

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Re: Periodontis bacteria linked to Alzheimer’s disease

Postby BrianR » Wed Jan 23, 2019 4:23 pm

Fiver wrote:Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors
http://advances.sciencemag.org/content/5/1/eaau3333

A couple of things from the conclusion might be of general interest [emphasis mine]:
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. ...

Also, FWIW, they speculate wildly about interactions with APOE4:
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.

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Re: Periodontis bacteria linked to Alzheimer’s disease

Postby Julie G » Wed Jan 23, 2019 5:16 pm

Until the small molecule inhibitors are ready... a simple remedy in your kitchen?

Effect of coconut oil in plaque related gingivitis — A preliminary report
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382606/
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

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Re: Periodontis bacteria linked to Alzheimer’s disease

Postby antimatter37 » Wed Jan 23, 2019 5:38 pm

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?

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Re: Periodontis bacteria linked to Alzheimer’s disease

Postby Julie G » Wed Jan 23, 2019 6:53 pm

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?

Well, we have lots of evidence that E4 carriers have an impaired BBB... Here's a recent paper.

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Re: Periodontis bacteria linked to Alzheimer’s disease

Postby Fiver » Thu Jan 24, 2019 8:41 am

And....viruses are so tiny. And some move inside of nerve cell projections, or along them. I tend to think of the BBB as a way to slow down pathogens, so the immune system inside can keep up without being over-run.
Four relatives with AD. Concerned, but hopeful. Introverted, but will talk about science.

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Re: Periodontis bacteria linked to Alzheimer’s disease

Postby Jaque » Thu Jan 24, 2019 11:01 pm

The pharma company involved in this research is:
https://www.cortexyme.com/

"COR388 is a promising drug for the treatment of AD with a novel mechanism of action. COR388 is readily bioavailable after oral administration with a favorable PK profile. COR388 was safe and well tolerated by older subjects and patients with AD when given at doses ranging from 25 to 100 mg for up to 28 days. There was a trend of improvement in some of the cognitive tests of the AD patients treated with COR388 HCl in this study, however, these results should be interpreted with caution due to the small sample size. Cortexyme is planning to initiate a large phase 2 study of COR388 in mild to moderate AD in 2019."

Anyone interested in taking part in their phase 2/3 trials can register on the company's website.

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Re: Periodontis bacteria linked to Alzheimer’s disease

Postby J11 » Sat Jan 26, 2019 4:37 pm

Hmm, also in terms of realigning what we thought we knew about AD, perhaps the ketogenic diet is not so much about ketones as about oral bacteria. Recently, I finally pushed myself to try a 0 carb diet for a week. I was eating about 2,000 calories per day, though it felt like starvation.

One of the most noticeable effects after finishing the week was how clean my teeth felt. This should not be surprising. The bacteria in your mouth live on carbs. No carbs --> Problem for the bugs. Of course, I also threw everything else I had in my dental tool kit including: Water flosser loaded with Periogen, sonic toothbrush, Theobromine toothpaste, ionic toothbrush, oral Probiotics etc.
If solving AD only requires exceptional dental hygiene, then I'm set.

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."

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

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Re: Periodontis bacteria linked to Alzheimer’s disease

Postby circular » Sat Jan 26, 2019 4:43 pm

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."

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

Crazy, not long ago I posted about an issue with a microorganism found in cats and cat owners and AD. Can't pull it up for some reason.
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Re: Periodontis bacteria linked to Alzheimer’s disease

Postby J11 » Sat Jan 26, 2019 4:45 pm

circ, the people are here to help!

https://en.wikipedia.org/wiki/Toxoplasma_gondii


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