Epistemic status: Big if true, I don't have much time now but I might try and write part of this up into a more formal scientific letter to a journal or something later. I am reasonably confident that my models here are significant in some way but I do not have much experience in the field and I've written this up over the past weekend instead of revising for my exams.

This is a follow-up to my first post, which compared Tau and Aβ proteins with mHTT to assess whether rapidly turning-over proteins can cause diseases on a long timescale.


In this post I will assess the various evidence we have for what the causal chain for AD might be, what might be "upstream" of what, and what we might draw as conclusions.


Hyperphosphorylated Tau protein can both promote Tau aggregation, and be toxic. Hyperphosphorylation of Tau protein is increased by problems with glucose metabolism in mitochondria, which is an early indicator of AD. This is because OGclNAcylation of Tau depends on mitochondrial activity, and prevents Hyperphosphorylation. (1)(2)

Mitochondrial mutations can accumulate throughout life, and mitochondrial mutations are a hallmark of ageing.(3)

Individuals with certain Aβ mutations develop AD at very young ages, but Aβ plaques often accumulate long before the disease shows.(4)

PGC-1α is a protein involved with increasing levels of mitochondria. This is known as mitochondrial biogenesis. EET-A is a molecule which acts as an agonist for PGC-1α (in mouse models).(5)

mHTT acts as an antagonist for PGC-1α. Tau proteins have been implicated in HD.(6)(7)

EET-A reduces Aβ plaque formation in a mouse model of AD.(8)

My Current Model

Mitochondrial mutations can build up over time, particularly with ageing. In some individuals with various other problems (insulin insensitivity in the brain, genetic predisposition) this causes mitochondrial glucose metabolism in neurons to drop below a certain threshold. This leads to decreased OGlcNAcylation of Tau protein, which leads to hyperphosphorylation of Tau protein. This leads to Tau toxicity and accumulation. 

I do not currently have a prediction of the mechanism by which this leads to Aβ plaque (and smaller soluble aggregate) formation but I believe the empirical evidence for this is strong. 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. causes some effect higher up the causal chain of AD (I think pinning the effect onto glucose metabolism is probably too specific a cause, and some studies have suggested Aβ plaques affect Tau hyperphosphorylation. This explains why AD can be caused eventually by excessive Aβ aggregation. The presence of a feedback loop is in some ways expected, as it helps to explain why the disease progresses rather than simply stalling.

mHTT decreases PGC-1α expression which feeds directly into the Tau protein problems. I do not now why Aβ plaques have not been observed in HD patients. Perhaps it is simply that HD progresses rapidly without the need for Aβ plaque formation, so there is not time for them to build up. Perhaps it is due to more complexity in the distribution of these proteins throughout the brain, both within and between cells. Perhaps this model is incomplete or very wrong.

Increasing PGC-1α expression is able to provide enough mitochondrial activity that OGlcNAcylation of Tau resumes to a high enough level that hyperphosphorylation of Tau decreases enough to prevent the whole cascade from occurring.

EET-A seems to be doing well in many trials of regeneration-like medicine, I suspect it will have potential (or something like it will) as part of an anti-ageing therapy.

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  1. Gong, C.-X., Liu, F., Grundke-Iqbal, I., & Iqbal, K. (2006). Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation [JB]. Journal of Alzheimer’s Disease, 9(1), 1–12. https://doi.org/10.3233/JAD-2006-9101
  2. Gong, C.-X., & Iqbal, K. (2008). Hyperphosphorylation of Microtubule-Associated Protein Tau: A Promising Therapeutic Target for Alzheimer Disease. Current Medicinal Chemistry, 15(23), 2321–2328. https://doi.org/10.2174/092986708785909111
  3. Sun, N., Youle, R. J., & Finkel, T. (2016). The Mitochondrial Basis of Aging. Molecular Cell, 61(5), 654–666. https://doi.org/10.1016/j.molcel.2016.01.028
  4. Bateman, R. J., Xiong, C., Benzinger, T. L. S., Fagan, A. M., Goate, A., Fox, N. C., Marcus, D. S., Cairns, N. J., Xie, X., Blazey, T. M., Holtzman, D. M., Santacruz, A., Buckles, V., Oliver, A., Moulder, K., Aisen, P. S., Ghetti, B., Klunk, W. E., McDade, E., … Morris, J. C. (2012). Clinical and Biomarker Changes in Dominantly Inherited Alzheimer’s Disease. New England Journal of Medicine, 367(9), 795–804. https://doi.org/10.1056/nejmoa120275
  5. Singh, S. P., Schragenheim, J., Cao, J., Falck, J. R., Abraham, N. G., & Bellner, L. (2016). PGC-1 alpha regulates HO-1 expression, mitochondrial dynamics and biogenesis: Role of epoxyeicosatrienoic acid. Prostaglandins & Other Lipid Mediators, 125, 8–18. https://doi.org/10.1016/j.prostaglandins.2016.07.004
  6. Johri, A., Chandra, A., & Flint Beal, M. (2013). PGC-1α, mitochondrial dysfunction, and Huntington’s disease. Free Radical Biology and Medicine, 62, 37–46. https://doi.org/10.1016/j.freeradbiomed.2013.04.016
  7. Vuono, R., Winder-Rhodes, S., de Silva, R., Cisbani, G., Drouin-Ouellet, J., Spillantini, M. G., Cicchetti, F., & Barker, R. A. (2015). The role of tau in the pathological process and clinical expression of Huntington’s disease. Brain, 138(7), 1907–1918. https://doi.org/10.1093/brain/awv107
  8. Chen, W., Wang, M., Zhu, M., Xiong, W., Qin, X., & Zhu, X. (2020). 14,15-Epoxyeicosatrienoic Acid Alleviates Pathology in a Mouse Model of Alzheimer’s Disease. The Journal of Neuroscience, 40(42), 8188–8203. https://doi.org/10.1523/jneurosci.1246-20.2020


2 comments, sorted by Click to highlight new comments since: Today at 11:10 PM
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This is an interesting idea and I appreciate you putting this together. A few comments: 

  1. 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?
  2. 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?
  3. 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!

  1. You may be right there, and I would certainly be pleased to hear of any projects like this.
  2. 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.
  3. 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.