Alzheimer’s Disease – taking over the brain

My first blog was about a transmissible form of cancer in dogs, Tasmanian devils and clams (Transmissible Cancer). This time I’m going to explain about the transmission of Alzheimer’s Disease but don’t worry, I don’t mean the transmission between people, that can’t happen. I mean the progression and spread of the disease to different parts of the brain. In my last post (Alzheimer’s Disease), I talked about the basic pathology of the disease and how it is thought the build-up of misfolded proteins (tau and amyloid β) cause the nasty memory loss symptoms. This build-up first occurs in areas important for short-term learning and memory, thinking and planning, namely the hippocampus, and it often happens before any symptoms are detected. In mild Alzheimer’s Disease, the damage spreads to other regions of the brain including areas important for spatial awareness and speech. In late stages of the disease, the pathology can be found in many areas. The associated cell death causes significant shrinkage in brain size.

But how do these misfolded proteins spread? Well… this has puzzled scientists for a while. Recently, I went to an Alzheimer’s Research UK day with really interesting talks from top researchers in this area. Dr Amy Pooler, who worked at King’s College London, explained about some of her research into how tau protein ‘jumps’ between neurons.

As you might already know, neurons signal to each other using chemicals called neurotransmitters, which are released from the end of one neuron, pass across a tiny gap (called a synapse) and are taken up by specific receptors on another neurone. Dr Pooler and her colleagues found that tau is released from neurons when they signal to each other. This tau is then somehow taken up by other cells. They discovered this when they stopped one neuron’s ability to produce its own tau. They then stimulated a signal from another neuron and found that, lo and behold, the first neuron contained tau even though it couldn’t produce its own. The mechanism is still unclear, but it does seem that the transmission of tau requires a functioning synapse. This might not seem significant, but it proves that a functioning neural connection is required for the disease to spread and it is not simply cell death and the bursting of cells. This is an important finding as it gets us one step closer to understanding how the pathology spreads to other brain regions.

However, this isn’t the full story. Professor Goedert from the University of Cambridge hypothesises that the spread is ‘prion like’. Let me explain what that means: a prion is basically an infectious protein. When an abnormal protein moves from one cell to another cell, the abnormal protein becomes the dominant force in the new cell. It seems to take over the normal version of the same protein, disrupting normal cell processes. There are still a lot of unknowns about why this happens. Is normal protein being converted into abnormal, or is abnormal protein being produced from scratch?

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The dark purple clumps are tau tangles, in the brain of a patient with Alzheimer’s Disease.(By Patho – own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=20016547 )

We already know about prion neurodegenerative diseases like Kuru and Creutzfeldt-Jakob disease which are ‘transmissible’ through the brain. Prof Goedert suspects that Alzheimer’s Disease and abnormal, bad tau spreads like this too (remember normal tau is still required for proper neuronal signalling, it’s the abnormal tau that is so destructive). He backed up this theory by injecting a misfolded tau protein into a mouse. It was found that the mouse began to develop tau pathology of its own in the injected brain region. Not only this, but over time the disease pathology spread to other parts of the brain. More needs to be learned about how this process occurs, but cracking the mechanisms could provide a great area for new treatments. Being able to stop the spread of the disease early on could mean vital areas of the brain are saved.

As per usual with most biology, the bottom line is that nobody knowwwwsss – yet! People have good ideas about the spread of Alzheimer’s around the brain, but a lot more firm evidence is required before we can understand how, why and where this happens. And also why only certain neurones are affected. But maybe I’ll leave that for the next post!

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Alzheimer’s Disease

Alzheimer’s disease is a horrible, degenerative disease of the brain where neurones become dysfunctional and eventually die. The biggest risk factor for the disease is clearly age – nearly half of everyone over 85 has Alzheimer’s and your risk increases greatly after the age of 65. People still don’t really understand why age is such a big factor, but I think that cracking this could reveal a whole range of new treatments.
Age isn’t the only risk factor. In a genetic, inherited form of the disease, symptoms can appear as early as 30.

In this post I’m going to try and explain some of the changes that occur at a cellular level in the brain when Alzheimer’s Disease is present. But you’ll realise that largely, the real cause of the changes that occur in the brain have only been guessed at.

The first sign of the disease is the presence of two abnormal proteins aggregating. Monomers (individual molecules) of a protein called Amyloid beta bind together to form larger oligomers and eventually aggregate into plaques in the extracellular space (outside of the neurones). It is not known what amyloid beta’s normal function in the body is, but plaques are a common pathological marker for AD.
The other protein is tau and is what our lab mainly focusses on. Normally, tau is found bound to microtubules – the structures in cells involved in transport. Microtubules act as a kind of conveyer belt, transporting proteins from one end of the cell to the other. This is especially important in long neurones where the cell body (where proteins are generally made) could be meters away from the synapses (where most of the signalling occurs). Tau stabilizes these microtubule structures to allow for normal axonal transport – the transportation of proteins along the cell. In Alzheimer’s disease, the protein is modified and can no longer perform this function, meaning transport is disrupted and neurones can no longer properly signal. Tau also aggregates, but into ‘tangles’ inside the cell.

The disruption of normal cellular function – probably because of these two proteins causing trouble – can eventually lead to cell death and the grim symptoms that come with Alzheimer’s disease.
An example of a group of drugs on the market for treatment at the moment are ‘cholinesterase inhibitors’. They work by increasing the levels of signalling between neurones.
Another novel drug, undergoing clinical trials at the moment (which was also researched in our lab) works by re-stabilizing the microtubules to try and re-establish axonal transport.

Although current treatments are semi-successful at reducing symptoms, there is still an urgent need for a cure, especially with the rising older population. This is not a simple task, seeing as we still don’t have a deep understanding of the exact causes of the disease.
But this isn’t the only issue: it is now believed that pathological signs of the disease may actually appear up to 20 years before any symptoms even arise. This adds another level of complexity to curing the disease as it would require identification of changes in the brain when a seemingly healthy person is quite young.

Research groups around the world are working hard towards the common goal of finding a cure, but first the mysteries of what exactly causes this disease, as well as early risk factor markers, must be fully uncovered!

I wrote this post, then found a video, so just watch this if you can’t be bothered to read, it’s very good: