The tangles of tau - breaking down highways

In a stereotypical brain from an Alzheimer's patient, there is the presence of amyloid plaque and tau tangles. We have already covered amyloid deposits in a previous post. Today, we will be discussing this tau thing. What is it? And, what the heck does it have to do with Alzheimer's Disease?

What is the link between Alzheimer's Disease and tau protein?

Post-mortem brains from Alzheimer's patients often have tau tangles (also called neurofibrillary tangles. The pictures below shows a magnified version of what these tangles look like (tau tangles are on the right, amyloid deposits on the left).

Image taken from bigthink.com

What are tau tangles aka neurofibrillary tangles?

These tangles are composed of a bunch of abnormal tau protein stuck together.

What is tau? why does it clump together during Alzheimer's Disease?

In order to answer this question, I think we should first go over what microtubules are. Microtubules allow the transport of materials across the neurons.

Here is an analogy - if your neuron is a city, then microtubules are the roads. You see, your neuron is constantly making stuff that it needs to send to different parts of the cell. One way to do that would be to simply make something and let it diffuse through the cell. But, this would not be very efficient. Therefore, the cell sets up it's own roadways in order to keep delivery organized and efficient.

Here's the really neat thing. These roadways are entirely dynamic! If the cell is done sending one protein to one part of the cell, it can send workers to that road and break down that roadway.

From Nature Reviews

And this is where tau becomes important. You see, what tau does, it helps the workers know whether or not to break a highway down. Sort of like a beacon to say - this road needs to stay!

Microtubules - the roadway of cells. (Image taken from absoluterights.com)

What happens to tau in AD?

Tau gets hyperphosphorylated in AD.

Wait, stop using big words, you showoff. What does that 'phosphorylation' mean?

Phosphorylation occurs when a phosphate group is thrown onto a protein.

Every protein in every cell of your body is under tight control. This is because, evolution has ensured that every protein can be made, destroyed or made to disappear as the cell needs it. Phosphorylation is one of these regulatory processes. By throwing a phosphate group onto a protein, you can change what that protein is doing.

Okay, what does phosphorylation do to tau?

Well, here's the weird thing about tau, it can exist in three forms---

1. Unphosphorylated - this is the form we have been talking about - when this form is present, the cell knows that that roadway needs to stay.

2. Phosphorylated - This is the green signal for the roadway to be taken apart. Let me reiterate, that this is normal. This phosphorylation-unphosphorylation allows the dynamic rearrangement of the roads in the cell.

3. Hyperphosphorylated - This is bad news bears. This is when the tau starts to misbehave and clumps together.

Okay, this is getting too sciency again. What are you even talking about?

Here's the gist so far - Tau is important to maintain normal function in the cell. During Alzheimer's this protein gets too many phosphate groups put on it. This makes the cell lose a bunch of it's roadways for no good reason.

And, what's worse is that all that hyperphosphorylated tau starts to clump together and form those aforementioned tau tangles.

What do these tau tangles do that's so bad?

Just like the amyloid plaque story, this isn't so cut and dry. Many believe that these deposits lead downstream to neuronal death. And, as we've discussed earlier, neuronal death is a key component of the cognitive issues in Alzheimer's Disease.

Is there a link between this tau stuff and the a-beta stuff?

Yes, there have been many studies that show that a-beta can actually lead to tau hyperphosphorylation (the bad version of tau). There are also a small number of studies, that are studying whether the converse is true - that tau can affect a-beta production.

Can we reduce this hyperphosphorylation?

There have been attempts to target the things that regulate the phosphorylation of tau. These have had limited to no success.

Okay, I'm bored. Summarize this.

Okay, here goes. Tau itself is not bad. The neuron needs it. But, for reasons that remain unclear, tau converts to a form (hyperphosphorylated). And this form arguably leads to cell death. And that, in turn leads to the tau tangles we observe in the brains of Alzheimer's patients.


Let me know what you guys think. Did anything still seem confusing? Please reach out to me at @AlzBlog101 or @NipunChopra7 .