A Possible Metabolic Mechanism for Alzheimer’s

Alzheimer’s is a neurodegenerative disorder. It’s a prototypical disorder with symptoms of forgetfulness that everyone, from your parents to precocious ten year olds, could describe to you.

Interestingly, this paper caught my attention due to its link to insulin as a different, new mechanism of Alzheimer pathology. For most, Alzheimer’s molecular pathology is easy to remember because it is linked to extracellular amyloid plaques and intracellular neurofibrillary tangles comprised of tau proteins. This simplistic model of disease is characterized by two unmistakable microscopic characteristics. Strangely enough, this paper argued that insulin accumulation and resistance is a possible mechanism of a subset of Alzheimer’s patients.

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A beautiful picture of insulin accumulation along with hyperphosphorylated tau protein tagged by AT180. (All subsequent photo credits from paper)

Firstly, this paper substantiated the claim that tau protein hyperphosphorylation causes insulin accumulation. Many papers are satisfied with establishing correlation, but the cause and effect link is what really caught my eye. They did so by modifying mice genes and creating tau protein hyperphosphorylation states in mice. Then, they showed that tau protein hyperphosporylation leads to insulin pathology. Furthermore, the authors went on to show that insulin accumulation occurs in groups, that is they oligomerize, and that  the event eventually leads to insulin resistance.

To put things in perspective, until recently, people haven’t even thought insulin could cross the blood-brain barrier, a semi-permeable barrier to toxins and various hormones  akin to the Great Wall of China,. The idea that insulin could both enter the blood brain barrier and modulate pathways like MAPK/ERK which target learning, is fresh knowledge to both you and me as well as researchers. It underlies the idea that we don’t really understand much about insulin pathology, which is a really scary thought when we think of the overlap between many clinical patients who have both diabetes and Alzheimer’s. It is worrisome because these specific patients take insulin peripherally, along with medications targeting tau protein phosphorylation status and amyloid plaque formation.

In the researchers’ first tests, they established a correlation between Alzheimer’s and diabetes with a simple observation. They took an antibody, specific for insulin, and stained different tissues, some from deceased patients with Alzheimer’s and some from deceased patients without it.

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The beginning of an adventure: stained hippocampal neurons

What they saw under the microscope was clear. Those patients with Alzheimer’s disease had these darkly stained hippocampal neurons. They cut three different sections of the hippocampus, each within a certain area of the brain. Furthermore, they used a different type of microscope (confocal) to generate a fluorescent picture of insulin accumulation within the neuronal cells. The pan-neuronal stain in the middle is supposed to stain all the neurons and give you a an idea of the shape of the cell structures that exist there.

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Fluorescent staining of neurons (as beautiful as Picasso’s artworks)

Afterward, they established a link between hyperphosphorylated tau protein and insulin with a different specific antibody, showing that that the two both showed up in the same place. The large degree of overlap between the two implies a relationship – maybe one leads to another or vice-versa.

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AT180 shows up a lot in this paper – it stains hyperphosphorylated tau protein, the pinned instigator of insulin accumulation.

Moreover, what I also really loved about this paper was the rigorousness with which they systematically ruled out possible alternative hypothesis that could confound their experiments. Interestingly, a specific example stood out to me as a clear possibility – type two diabetes is also prevalent within these populations which could inflate insulin levels in the brain. So, as if they predicted my questions before I asked them, they presented a figure comparing insulin levels specifically in the brain between those with type two diabetes (diabetes mellitus), those with Alzheimer’s, and different combinations of the two.

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Looking at diabetes mellitus and it’s effect on insulin in the brain. Sometimes you just want to hug researchers for their meticulousness and hardwork.

For me, another interesting aspect of the paper was the idea that you could pull proteins stuck together, called oligomers, with certain chemical solutions. The ones they tested, PBS, SDS, and formic acid, removed monomers, soluble oligomers, insoluble oligomers, and fibrillary formations (which I assume to be comprised of intermediate filaments, microfilaments etc.). Formic acid was shown to have more dissolved insulin in it, which gives rise to the idea that the insulin subunits were hugging each other (oligomerizing in solution).

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I’m taking a guess that they soaked certain portions of the brain in PBS, (a buffer solution of salts – like salt water) SDS, (a detergent) and formic acid (of which I have no idea what it does normally)

Lastly, I wanted to take a second to appreciate that the authors looked at other tauopathies (problems with the tau protein) that extended past Alzheimer’s disease. They looked at tauopathies in PSP, a Parkinson-like disease which is characterized by tau protein accumulation in glial cells, cells that support the neurons.

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Another confocal image, this time as you go across the row, you see different tau pathologies that are not Alzheimer’s. Tau pathology has relevance in a couple other diseases as well.

Ultimately, you can pick out the antibody staining of hyperphosphorylated tau proteins in the second row by AT180, a similar phosphorylation state to that in Alzheimer’s disease.

Unfortunately, I can’t do a long write-up like this everyday, but I really enjoyed reading this paper on tau hyperphosphorylation and it’s effects on insulin accumulation and resistance. While I didn’t really present too much information on the insulin aspect of the disease, I really liked the molecular techniques that they utilized and the experimental controls they used to support their hypothesis. I look forward to reading more on neurodegenerative disorders and I hope you learned something awesome!

Bibliography:

  1. Alexandre Bejanin, Daniel R Schonhaut, Renaud La Joie, Joel H Kramer, Suzanne L Baker, Natasha Sosa, Nagehan Ayakta, Averill Cantwell, Mustafa Janabi, Mariella Lauriola, James P O’Neil, Maria L Gorno-Tempini, Zachary A Miller, Howard J Rosen, Bruce L Miller, William J Jagust, Gil D Rabinovici; Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease, Brain, , awx243, https://doi.org/10.1093/brain/awx243

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