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.

Introduction

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.

Evidence

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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References

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