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Will Tau Tangles Research Unravel the Mystery of Alzheimer’s Disease?

By | September 4th, 2017

How does a disease like Alzheimer’s spread across the brain? Degenerative diseases including Alzheimer’s, Parkinson’s and other dementias are what is called prion-like, meaning they happen because proteins in the brain misfold and change their structure. Once one protein misfolds, the same process can spread to other parts of the brain, causing many cells to misfold. That results in what we call tau tangles. We spoke to Jeffrey Kordower, Ph.D., Director of Neurobiology at Rush University, about the correlation of tau tangles and brain degeneration, and how to prevent tau tangles from happening in the first place.

  • We have the ability to clear beta-amyloid plaques, but that doesn’t reverse or prevent memory loss. Scientists like Kordower are now looking at tau tangles as having a stronger correlation with Alzheimer’s
  • Immunotherapy may be one way to stop tau tangles from spreading, which uses antibodies to prevent the seed of one misfolded protein from traveling to another
  • Many drugs aimed at clearing tau are in phase three clinical trials

Watch Full Video Interview

Being Patient: You have done a lot of research into Parkinson’s Disease, but now you’re looking into the tau tangles. You are in the so-called “tau tangles camp”. Tell me a little bit about your research with tau and why you believe that tau may unlock a lot of the mystery around Alzheimer’s.

Jeffrey Kordower: I think many, if not all, degenerative diseases are what we call prion-like. They are due to proteins that are normally found in the brain and misfold for some reason. Then once they misfold, they’re able to spread from one place to another causing other cells to misfold. We believe that’s what’s involved with disease progression. We know in Alzheimer’s disease that the disease probably starts in the brain in a region sort of on the lower side of the brain called the entorhinal cortex. That area is filled with neurofibrillary tangles. If you take someone who’s got very early Alzheimer’s disease but still has memory and cognitive deficits, that’s the area that has the most degeneration. And that’s the area that has the most neurofibrillary tangles.

Being Patient: But hasn’t science been working on the presumption that the plaques come first followed by the tangles?

Jeffrey Kordower: We now have the ability to clear these plaques. But still when you clear these plaques nothing happens. You could say that maybe they’ve already done their damage and there’s nothing to protect. But I think that the correlation between plaque load and cognitive dysfunction is very poor. And the correlation of tau pathology is much better, and actually [so is] the correlation of what we call synaptology, where the neurons project to a different area and they connect. Those connections are probably the most that correlate with cognitive dysfunction. So that’s what we’re trying to get at with tau.

Being Patient: To what extent can we isolate how much damage has been caused postmortem in brain plaques versus tangles?

Jeffrey Kordower: You only get one snapshot in a postmortem brain. What you have to do is look at a lot of different brains that have a spread of cognitive dysfunction in the patient population that were generous enough to donate these brains.

What you do is you look at patients who just have mild Alzheimer’s disease, patients who have severe Alzheimer’s disease and a scattering of brains in the middle. Then you look at tau tangle load versus amyloid load and what you find is that the tau load is much more correlative with the cognitive dysfunction.

Being Patient: If tau is indeed confirmed to be a source of the damage of an Alzheimer’s brain, how does that change things and which direction would research go? What does it look like to prevent tau tangles?

Jeffrey Kordower: There are a number of approaches. The most popular one that’s emerging is called immunotherapy—to use antibodies to try and block the spread of what we call seeds. So what you have is a cell that makes abnormal tau. And that tau secretes into the extracellular space—the space between cells—a seed of abnormal tau. That [seed] is picked up by a second cell and that second cell starts generating more and more abnormal tau. And then it secretes a little seed. And so the same thing happens over and over again. If you can block this seeding from one cell to another, what we call propagation, you should be able to block the degeneration that’s taking place over long periods of time, and you should be able to prevent the onslaught of cognitive demise.

Being Patient: We know that there are some tau drugs being tested right now. They’re in clinical three trials. Where are we in knowing whether the philosophy that a lot of the tau camp is betting on is right?

Jeffrey Kordower: Normally tau would not misfold because there are organelles or parts of the cell that clear unwanted proteins. So, sort of like your garbage disposal. You know, you put something in, you grind it up and it goes away. But what happens is with tau and other misfolded proteins like alpha synuclein, these garbage disposals in the cell stop working and you get more and more of the tau built up. There are a number of ways to try and reduce tau and prevent that from happening. Some of these drugs may be trying to enhance the ability for the garbage disposal to work better. I’m not sure of the timelines that are ongoing at the moment with these tau drugs. But a phase three clinical trial is basically the step before going into therapy. So we’re hopeful that they’ll be successful.

Being Patient: Is there anything that we’ve learned from diseases such as Parkinson’s that could help us with Alzheimer’s disease?

Jeffrey Kordower: The idea that misfolded proteins propagate came originally from Parkinson’s disease. And this protein called alpha synuclien, which is normally found at the connection point between two cells, becomes misfolded and does this song and dance with these seeds to go across and propagate across the entire brain. And so people thought from there maybe tau and maybe amyloid can propagate from cell to cell. So these are very active areas of research.


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