You may be right there, and I would certainly be pleased to hear of any projects like this.
I believe the model could work without it, but AD seems to be an attractive state that many human brains fall into with various genetic associations. The main evidence for it is that mutations in Aβ precursor protein can have very high penetrance (i.e. everyone who has the mutation develops early-onset AD (https://link.springer.com/content/pdf/10.1007/s11920-000-0061-z.pdf). You are definitely right that I was too specific in my assessment of exactly how Aβ plaques cause a feedback mechanism, thanks for catching that. I have amended the post to fix that.
Lastly what do you mean specifically by prion-like? Amyloid fibrils are a prion-like structure in the sense that the growth of existing fibres is much, much more favourable than the formation of new ones. (this leads to exponential growth as long fibres break apart leaving new open ends for new protein molecules to add) However Aβ plaque formation was reversed in the mice given EET-A which means that at some physiologically achievable concentrations of free Aβ, the amyloids dissipate due to un-misfolding of Aβ (at least in mouse models). This would suggest that the cause of AD is various factors pushing the brain over a threshold where Aβ can accumulate. (which could be metabolic, or mutations which make Aβ more likely to accumulate) This is in contrast to “classical” prions where the original misfolded protein is able to continuously cause the misfolding of normal protein at normal physiological conditions, and the only barrier to a prion disease occurring is that no misfolded protein is present.
The paper which you sent also postulates a feedback loop between Aβ and Tau which is interesting. I had considered the Aβ feedback into the earlier mechanism as an afterthought but perhaps it is more important than my model suggested.
Thanks for the feedback!
You may be right there, and I would certainly be pleased to hear of any projects like this.
I believe the model could work without it, but AD seems to be an attractive state that many human brains fall into with various genetic associations. The main evidence for it is that mutations in Aβ precursor protein can have very high penetrance (i.e. everyone who has the mutation develops early-onset AD (https://link.springer.com/content/pdf/10.1007/s11920-000-0061-z.pdf). You are definitely right that I was too specific in my assessment of exactly how Aβ plaques cause a feedback mechanism, thanks for catching that. I have amended the post to fix that.
Lastly what do you mean specifically by prion-like? Amyloid fibrils are a prion-like structure in the sense that the growth of existing fibres is much, much more favourable than the formation of new ones. (this leads to exponential growth as long fibres break apart leaving new open ends for new protein molecules to add) However Aβ plaque formation was reversed in the mice given EET-A which means that at some physiologically achievable concentrations of free Aβ, the amyloids dissipate due to un-misfolding of Aβ (at least in mouse models). This would suggest that the cause of AD is various factors pushing the brain over a threshold where Aβ can accumulate. (which could be metabolic, or mutations which make Aβ more likely to accumulate) This is in contrast to “classical” prions where the original misfolded protein is able to continuously cause the misfolding of normal protein at normal physiological conditions, and the only barrier to a prion disease occurring is that no misfolded protein is present.
The paper which you sent also postulates a feedback loop between Aβ and Tau which is interesting. I had considered the Aβ feedback into the earlier mechanism as an afterthought but perhaps it is more important than my model suggested.