What is tau in Alzheimer’s disease? Why is it relevant and how does it affect the development of the disease.
Let’s find out.
Most people not familiar with the molecular underpinnings of dementia will have never heard of tau. This is surprising since tau is one, if not the critical protein for developing Alzheimer’s disease – and actually a whole host of other dementias. In this article, we will focus on how tau contributes to/causes Alzheimer’s disease, the most common form of dementia. If you read this article, then I recommend also reading the sister entry on beta-amyloid here, which explain the other protein critical for the development of Alzheimer’s disease.
But let’s start from the beginning what is tau?
Tau is, of course, the 19th letter in the ancient Greek alphabet but in this context refers to a class of proteins – the tau proteins. Tau proteins have a whole host of different functions in the body, from regulating the protein synthesis in cells to regeneration processes. But in the context of Alzheimer’s disease, we are interested in one particular function, that of its work with the microtubule associated protein (short MAPT). I know, long words already, but let’s unpack this terminology.
As the name gives away the microtubule associated protein is associated with microtubules… Duh! you might say to this tautology but it makes clear that one cell structure – microtubules – plays an important part in the development of Alzheimer’s disease.
So, what are microtubules?
Microtubules are tiny tubes (micro = small, tiny; tubules = small tubes; so literally translated ‘small, small tubes’ which gives an indication of how tiny these tubes are). These microtubules can be found in many of our cells but in particular in our nerve cells (neurons). More specifically, the microtubules have their highest concentration in one part of the nerve cells, the axon. The axon is the part of the nerve cells that transmits the nerve signal from one nerve cells to another nerve cell. Some nerve cells have short axons (a few micrometres long), while other nerve cells can have long axons (several centimetres up to a meter long – the longest axons can be found in the sciatic nerve in our back). These axons are critical for our nerve cells to communicate with each other, as the axons allow us to send electric signals between nerve cells, allowing all our everyday activities, from seeing to moving to thinking. After all these years as a neuroscientist, I am still amazed that this electric signalling of nerve cells allows us all these functions.
But what is the function of the microtubules in the axons of the nerve cells?
The microtubules have two main functions in the axons of the nerve cells: 1) to give the axon stability; 2) to transport nutrients and other ‘stuff’ from one part of the axon to another part of the axon. Both these functions become compromised/disrupted when Alzheimer’s disease develops, so it is important that we understand these functions in more detail.
The microtubules, as I said, are small tubes and those tubes form part of the cytoskeleton of the cell. Cytoskeleton means literally the skeleton of the cell (cyto = Greek for cell). Now, cells don’t have bones but still need to be kept upright/intact. The cells use therefore different structures within them to keep themselves upright/intact. Microtubules are ideal for that since these tubes give great stability to the cell and particularly the axon which is very thin and not many other structures of the cytoskeleton would fit into it. So, just by being there, microtubules give the axon stability and allow the axon to work properly. It seems a pretty dull function just by ‘being there’ but like any wall or pillar within a building, these structures are critical so that the building does not collapse. But the microtubules have also a more exciting and, in my opinion, ingenious function – transport.
Nerve cells require to have nutrients and other critical materials moved through the cell. For that, the nerve cells require a transport system to move those nutrients and material around. It is the microtubules that are part of this transport system. The microtubules can literally transport any ‘stuff’ and with stuff I mean stuff. It doesn’t matter if it is nutrients, parts of cells or even whole organelles (organs of the cells), the microtubules can move it. In essence, the microtubules are like haulage companies that move goods from one part of the country to the other, except that the microtubules do this inside of the nerve cells and specifically in the axons of the nerve cells.
How do the microtubules transport ‘stuff’?
One would assume that the stuff to be transported would go through the tubes of the microtubules but that is in fact wrong. The reason why stuff is not transported through the microtubules is that these tubes are indeed tiny and it would, therefore, limit what we can transport through these tubes. The limit would be determined by the diameter of the tubes and would make them, therefore, not very useful to transport most things in the cell – since we know already that they can transport pretty much anything from small molecules to large parts of the cells, much bigger than the size of the whole microtubule. Instead, microtubules transport their stuff on the outside of the microtubules. They do that by attaching anything that needs to be transported to the outside of the microtubules.
One can compare it to a roof rack we might install on our car to transport any stuff – one can even transport things that might be much bigger than the car, although not sure that should be recommended practically. To transport specific things on our car roof rack we might also have specific attachments for the roof racks, such as bicycle, ski, kayak attachments or a roof box. The same applies again to the microtubules which have specific attachments for different ‘stuff’ the transport, which means it is secure to transport until it reaches its destination.
So, we now know that microtubules are critical for the structure/skeleton of the cell and the transport of any molecules of nutrients across the cell. But before we explore how this is all relevant for Alzheimer’s disease we need to understand one final element – how do the microtubules actually move across the cell?
“I like to move it, move it”
To understand how microtubules move we have to stretch our imagination even further, as this mechanism is indeed ridiculously ingenious and I still marvel at how it works. Now, the microtubules don’t have legs or wheels to move from one part of the cell to another. Instead, they function more like a conveyor belt – a 3D conveyor belt. The outside of the microtubules can be compared to the transport band of the conveyor belt. But critically, the microtubules are not static conveyor belts but it is moving conveyor belt. Confusing isn’t it?
How can a conveyor belt move?
As I said we need to stretch our imagination here a bit. Imagine we had a conveyor belt to which we would add elements to the front while at the same time taking elements from the back. The conveyor belt would ‘move’ towards the direction we add elements to it while moving away from where we take elements away. This is how microtubules move as well. They add elements towards the direction they want to move towards while taking elements away from the direction they want to move away from. Pretty amazing, isn’t it? Even more amazing this allows the microtubules to move from across the cells to any place since they are not static.
That’s all very interesting, but what has that to do with tau or Alzheimer’s disease?
Relevance for Alzheimer’s disease
As so often in my articles, we need to first understand the basic biology f the brain before we can understand how Alzheimer’s disease affects these healthy processes. Now, the relevance of the microtubules in the generation of Alzheimer’s disease is due to the fact that tau is a critical protein for microtubules to work properly. In particular, the microtubules needs tau for their two main functions: The first is that tau is needed to attach the molecules the microtubules need to transport. Tau plays an important role in this attachment and if it does not work properly the molecules do not get properly attached and cannot be transported. The second function is that tau is needed for adding new elements to the microtubules when it is moving. For both functions, we can think of tau as a staple that allows attaching new elements to microtubules. If this tau staple fails, the microtubule cannot transport or even move across the cell anymore. Even worse, the microtubules start to disintegrate as the tau staples are not functioning properly. This is an awful scenario for the cell. Remember the cell needs microtubules to move stuff from one part to another. If this transport stops, we can compare it to a strike of the haulage industry in a country. The whole country would come to a standstill as goods cannot be transported anymore. The same applies to the cell as it does not get anymore the materials or nutrients it requires in different parts of the cell. This means that the cells dysfunction or even starve as nutrients don’t reach their destinations anymore.
On top of that, remember that the microtubules have also an important function to give structure or a skeleton to the cell. Once the microtubules start disintegrating, it also means that the structure of the cell gets affected and it can even collapse. We know already that the microtubules are very common in the axon of the nerve cells, which is a key structure for the communication of nerve cells. However, the disintegration of the microtubules in the axons means that those axons start to starve and collapse, affecting communication between nerve cells. Now, if this would happen to the odd nerve cell our brain would cope with that, however, in Alzheimer’s disease, this process seems to start in just a few nerve cells but then ‘propagates’ across nerve cells until – at the end of the disease – nearly all of the nerve cells in the brain are affected by this disintegration of the microtubules caused by tau. The reason why this process seems to propagate or affect other nerve cells is not yet entirely clear, click here to read an article on that topic.
Another critical aspect is that the nerve cell death leads to an increased release of tau into the brain and the cerebrospinal fluid, which surrounds the brain. This means that people who have Alzheimer’s disease show raised tau levels in cerebrospinal fluid or even blood, as all the tau has been released from the dying nerve cells. These raised tau levels are, therefore, a key diagnostic marker for any form of Alzheimer’s disease.
The other questions are then what actually causes the disintegration of microtubules? Why can the tau not staple itself anymore to the microtubules?
The exact reasons for this are still being explored and are, obviously, a key treatment target for any future Alzheimer’s disease medication developments. One key element in this process seems to be the molecule phosphate. Phosphate is required for tau to staple itself to the microtubules but, for yet unknown reasons, in Alzheimer’s disease, too much phosphate is around, which actually hinders or stops tau to attach itself to the microtubule. As I said, it is not yet entirely clear whether this is the only reason but it seems one key factor that is now a key target for Alzheimer drug development.
In summary, tau is a key protein in the development of Alzheimer’s disease. Tau has important functions in the healthy functioning of nerve cells in our brain, in particular in a structure called the axon, which is important for the communication between nerve cells. Specifically, tau is important in the structure of microtubules by binding/stapling microtubules components together. Microtubules can be seen as somewhat of a ‘haulage industry’ of the nerve cell, moving anything, such as nutrients and cell components from one part to another part of the nerve cell. The second function microtubules have is to provide structure to the nerve cells/axons – they are part of the cell’s skeleton. In Alzheimer’s disease tau does not bind to the microtubules anymore properly -for yet to be explored reasons, even though the abundance of the molecule phosphate seems a key factor for this. The failure of tau to bind to the microtubules means that the microtubules do not function anymore or even start to disintegrate. This has devastating consequences for the function of the nerve cells as nutrients and other cell components cannot be transported anymore and it starts to structurally collapse – remember the microtubules are key components of the cell’s skeleton. This leads to the nerve cell misfunctioning and in the end dying. One other curious aspect of tau is that it seems to propagate or ‘infect’ other nerve cells and hence an increasing amount of nerve cells are affected by this microtubule collapse and nerve cell death. With increasing nerve cell death we will have more symptoms as the brain does not function anymore properly, until nearly all our brain nerve cells are affected by this disease process at the end of Alzheimer’s disease.