This is an interesting idea and I appreciate you putting this together. A few comments:
I’m a bit skeptical of your comment in part 3 that “none of the biological/medical community has started doing something like this,” as that just seems unlikely to me. I’m less deeply involved in biology than it sounds like you are, but how confident are you that these kinds of modeling efforts don’t already exist?
You say “I also (without a mechanism) believe that Aβ plaques (and smaller soluble aggregates) have some feedback effect which further damages glucose metabolism in the brain.” How confident are you that this kind of feedback loop is really needed to make the model work? If the rest of your model holds true, could disease progression just be due to further mitochondrial damage occurring as people continue to age? And could AD tend to occur in people with excessive Aβ aggregation simply because this predisposes people to develop AD if they start having hyperphosphorylation of Tau proteins?
There’s some evidence that misfolded Aβ and Tau can have prion-like properties that can convert other Aβ and Tau into misfolded forms (https://sci-hub.se/10.1001/jamaneurol.2013.5847). Have you thought at all about how that might fit into the model?
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.
This is an interesting idea and I appreciate you putting this together. A few comments:
I’m a bit skeptical of your comment in part 3 that “none of the biological/medical community has started doing something like this,” as that just seems unlikely to me. I’m less deeply involved in biology than it sounds like you are, but how confident are you that these kinds of modeling efforts don’t already exist?
You say “I also (without a mechanism) believe that Aβ plaques (and smaller soluble aggregates) have some feedback effect which further damages glucose metabolism in the brain.” How confident are you that this kind of feedback loop is really needed to make the model work? If the rest of your model holds true, could disease progression just be due to further mitochondrial damage occurring as people continue to age? And could AD tend to occur in people with excessive Aβ aggregation simply because this predisposes people to develop AD if they start having hyperphosphorylation of Tau proteins?
There’s some evidence that misfolded Aβ and Tau can have prion-like properties that can convert other Aβ and Tau into misfolded forms (https://sci-hub.se/10.1001/jamaneurol.2013.5847). Have you thought at all about how that might fit into the model?
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.