Misfolded Proteins of Alzheimer’s Disease: Tau Protein

Way back in May, I introduced the topic of misfolded proteins in Alzheimer’s disease.

In the post called Developing new drugs for Alzheimer’s disease: Targeting Misfolded ProteinsI explained that the folded shape of a protein is critical to its function, and introduced the two misfolded proteins of Alzheimer’s disease: Beta-amyloid and Tau.

Up until now, I have only discussed Beta amyloid. Now it’s time to move on to the second misfiled protein in Alzheimer’s brain, hyperphosphorylated Tau.

Tau is a structural protein playing an important role in intracellular transport. Similar in function to railroad ties, it stabilizes microtubules in neuronal axons.

Microtubules do not carry a information, but they do transport a whole host of things necessary to the health and well-being of the cell. They move organelles like mitochondria from one place to another. They carry structural components to the locations that need them. They carry proteins needed for cellular metabolism.

In Alzheimer’s disease, the protein Tau, which normally binds to microtubules, gets twisted into short filaments that are unable to stabilize the tracks. When the microtubule network of the cell is destabilized, transport within the cell is disrupted. The twisted Tau filaments aggregate, forming intracellular deposits called neurofibrillary tangles. These can fill the entire cell, leading to the death of the neuron.

There are some drugs that prevent Tau misfolding and aggregation. In animal testing, these reduce tangle formation and  limit neuronal death, but so far none of them have made it past phase three clinical trials. The reason has generally been lack of efficacy–failure to produce cognitive and functional improvement–rather than issues related to toxicity.

As you can see, there are many approaches being taken to develop drugs that will fight Alzheimer’s disease. And each new fact discovered about the causes and progress of the disorder will lead to more avenues through which researchers can attempt to fight the disease.

This post concludes the series on drug development in Alzheimer’s disease. Once again, I will mention that information about specific drugs has come from the review Alzheimer’s disease: clinical trials and drug development, by Francesca Mangialasche, Alina Solomon, Bengt Winblad, Patrizia Mecocci, and Miia Kivipelto (Lancet Neurol 2010; 9: 702–16). Sources for background information have not been mentioned because the background is common knowledge among those of us who study this disorder. However, if you have specific questions, I will be happy to answer them or direct you to additional resources.

Tomorrow I begin a new job as Dean of Science at a small university here in Austin. I anticipate that the transition will result in a decrease in the number of posts I can produce each week. My plan is to continue this blog on a once a week schedule. My other blog, Transition Time, which has been a daily blog, will also move to once a week. Hope to see you there!

–Susan.

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5 thoughts on “Misfolded Proteins of Alzheimer’s Disease: Tau Protein

  1. Thank you for your considerably in depth posts. The picture of the trains colliding, spilling, irretrievably smashed, says a great deal. Best wishes and hugs for your new position as Dean – lucky students and faculty!

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    • Tau gets misfolded when too many phosphates are attached to it (hyperphosphorylation). There are many potential phosphorylation sites on the Tau protein. These sites are on the amino acids Serine and Threonine. But it is not the amino acids that are the problem. Serine and Threonine are essential to Tau’s normal function. The problem that twists the Tau out of shape is an excess of phosphates attached to those amino acids. And that is controlled by the actions of enzymes called Kinases and Phosphorylases, which are made by our cells. So altering the amount of Serine or Threonine in someone’s diet would not be a good idea. It could even backfire and make less normal tau available in the brain. General the best dietetic approach to Alzheimer’s is a good healthy diet, high in antioxidants.

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