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.
Introduction
It is sometimes said (often here, rarely in the places where it ought to be) that the turnover rate of amyloid-causing proteins in the brain is too high for them to be the primary causative agent of Alzheimer's disease (AD). While this is an important piece of evidence, I do not think it is as definitive as many suggest, due to biochemical reasons I will go into later. In order to investigate further I decided to compare AD to a better understood disease: Huntington's disease, and found an unexpected link in mechanism between the two. I have decided to write my findings up here.
This series of three posts will be rather scattered. This post aims to explain the motivations for my initial investigation, and also goes into some of the mathematics of amyloid formation. The next post will be a quick review of several pieces of evidence I have found and the assembly of this evidence into a (reasonably) cohesive model of AD progression. The third will be some predictions of mine based on this model, and a retrospective on the process of building this model.
Why turnover rates might not matter
The motivation for this investigation was to cement whether or not the high turnover rate of amyloid-causing proteins is strong evidence against them being causally involved in AD. The two amyloid-causing proteins are Tau and Amyloid Beta (Aβ). Tau forms aggregates inside neurons and turns over with a half-life of around 23 days in the central nervous system.(1) Aβ forms aggregates outside neurons and turns over even faster, with a half-life on the order of a few hours.(2)
There are some reasons why I thought that (counter-intuitively) that may not be the case. Cells in the body are generally under many layers of regulation, especially towards the concentration of different proteins, so rapid synthesis and degradation of proteins is not necessarily evidence that they can only cause diseases on long timescales. To see how this is relevant imagine the following model of an amyloid fibril:
Proteins are joined together into an amyloid fibril, they "fall off" the fibril at a rate of koff proteins per second. New proteins also join the amyloid fibril when they encounter it, but in this case the rate of proteins joining depends on the product of the concentration of free protein [P] as well as a new constant kon. This means the rate of growth of the fibril is kon[P]−koff proteins per second. If the cell maintains a concentration (or average concentration over time) of [P]=(1+ϵ)koffkon then we can see arbitrarily slow amyloid growth, which does not depend on rate of protein turnover. This model demonstrates that even proteins within the fibril (near the ends) can be replaced by other proteins, and fibrils also regularly break apart, exposing more proteins for turnover.
Huntington's Disease and Huntingtin
Huntington's Disease (HD), unlike AD, is a disease for which the causative agent is well known. The protein huntingtin (HTT) has a variable number of the amino acid glutamine at one end. If that number is too large (>35) the protein is now designated as mutant huntingtin (mHTT), which is thought to be toxic in its soluble form as well as forming aggregates. Whether the specific mechanism of toxicity is known or not does not particularly matter, because we do know that this is the ultimate cause (via genetic studies) HTT and mHTT both have half-lives in the tens of hours.(3) This demonstrates that relatively rapidly turning over proteins could potentially be the ultimate cause of long-term diseases.
Conclusion and Continuation
I expected to end this post here, discussing how perhaps the evidence isn't as strong as we suspected, and I was going to add a point about how certain Aβ mutations do cause AD (albeit with plaques forming up to 20 years before symptoms occur).(4) Then I managed to find a study into hyperphosphorylated Tau protein.(5) This gave me a lead which I was able to follow further up the causal chain. I will be posting a follow-up post to this giving more of my reasoning and some further conclusions on my current model of AD.
Sato, C., Barthélemy, N. R., Mawuenyega, K. G., Patterson, B. W., Gordon, B. A., Jockel-Balsarotti, J., Sullivan, M., Crisp, M. J., Kasten, T., Kirmess, K. M., Kanaan, N. M., Yarasheski, K. E., Baker-Nigh, A., Benzinger, T. L. S., Miller, T. M., Karch, C. M., & Bateman, R. J. (2018). Tau Kinetics in Neurons and the Human Central Nervous System. Neuron, 97(6), 1284-1298.e7. https://doi.org/10.1016/j.neuron.2018.02.015
Patterson, B. W., Elbert, D. L., Mawuenyega, K. G., Kasten, T., Ovod, V., Ma, S., Xiong, C., Chott, R., Yarasheski, K., Sigurdson, W., Zhang, L., Goate, A., Benzinger, T., Morris, J. C., Holtzman, D., & Bateman, R. J. (2015). Age and amyloid effects on human central nervous system amyloid-beta kinetics. Annals of Neurology, 78(3), 439–453. https://doi.org/10.1002/ana.2445410.1016/j.cell.2009.03.01
Jeong, H., Then, F., Melia, T. J., Jr., Mazzulli, J. R., Cui, L., Savas, J. N., Voisine, C., Paganetti, P., Tanese, N., Hart, A. C., Yamamoto, A., & Krainc, D. (2009). Acetylation Targets Mutant Huntingtin to Autophagosomes for Degradation. Cell, 137(1), 60–72. https://doi.org/10.1016/j.cell.2009.03.018
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/nejmoa1202753
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
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.
Introduction
It is sometimes said (often here, rarely in the places where it ought to be) that the turnover rate of amyloid-causing proteins in the brain is too high for them to be the primary causative agent of Alzheimer's disease (AD). While this is an important piece of evidence, I do not think it is as definitive as many suggest, due to biochemical reasons I will go into later. In order to investigate further I decided to compare AD to a better understood disease: Huntington's disease, and found an unexpected link in mechanism between the two. I have decided to write my findings up here.
This series of three posts will be rather scattered. This post aims to explain the motivations for my initial investigation, and also goes into some of the mathematics of amyloid formation. The next post will be a quick review of several pieces of evidence I have found and the assembly of this evidence into a (reasonably) cohesive model of AD progression. The third will be some predictions of mine based on this model, and a retrospective on the process of building this model.
Why turnover rates might not matter
The motivation for this investigation was to cement whether or not the high turnover rate of amyloid-causing proteins is strong evidence against them being causally involved in AD. The two amyloid-causing proteins are Tau and Amyloid Beta (Aβ). Tau forms aggregates inside neurons and turns over with a half-life of around 23 days in the central nervous system.(1) Aβ forms aggregates outside neurons and turns over even faster, with a half-life on the order of a few hours.(2)
There are some reasons why I thought that (counter-intuitively) that may not be the case. Cells in the body are generally under many layers of regulation, especially towards the concentration of different proteins, so rapid synthesis and degradation of proteins is not necessarily evidence that they can only cause diseases on long timescales. To see how this is relevant imagine the following model of an amyloid fibril:
Proteins are joined together into an amyloid fibril, they "fall off" the fibril at a rate of koff proteins per second. New proteins also join the amyloid fibril when they encounter it, but in this case the rate of proteins joining depends on the product of the concentration of free protein [P] as well as a new constant kon. This means the rate of growth of the fibril is kon[P]−koff proteins per second. If the cell maintains a concentration (or average concentration over time) of [P]=(1+ϵ)koffkon then we can see arbitrarily slow amyloid growth, which does not depend on rate of protein turnover. This model demonstrates that even proteins within the fibril (near the ends) can be replaced by other proteins, and fibrils also regularly break apart, exposing more proteins for turnover.
Huntington's Disease and Huntingtin
Huntington's Disease (HD), unlike AD, is a disease for which the causative agent is well known. The protein huntingtin (HTT) has a variable number of the amino acid glutamine at one end. If that number is too large (>35) the protein is now designated as mutant huntingtin (mHTT), which is thought to be toxic in its soluble form as well as forming aggregates. Whether the specific mechanism of toxicity is known or not does not particularly matter, because we do know that this is the ultimate cause (via genetic studies) HTT and mHTT both have half-lives in the tens of hours.(3) This demonstrates that relatively rapidly turning over proteins could potentially be the ultimate cause of long-term diseases.
Conclusion and Continuation
I expected to end this post here, discussing how perhaps the evidence isn't as strong as we suspected, and I was going to add a point about how certain Aβ mutations do cause AD (albeit with plaques forming up to 20 years before symptoms occur).(4) Then I managed to find a study into hyperphosphorylated Tau protein.(5) This gave me a lead which I was able to follow further up the causal chain. I will be posting a follow-up post to this giving more of my reasoning and some further conclusions on my current model of AD.
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