A link between neurodegenerative diseases?

I have talked a lot about Alzheimer’s Disease and how we think it progresses as a neurodegenerative disease etc. This time I’m going to talk about another neurodegenerative disease – Parkinson’s disease. Like in Alzheimer’s, Parkinson’s Disease has worsening symptoms as it progresses because of increasing levels of neuronal damage. It is mainly a motor disorder where control over movement is lost.

Parkinson’s is also caused by the build-up of a misfolded protein called α-synuclein. This protein can stick (or aggregate) together to form build-ups called Lewy Bodies. In Alzheimer’s, Tau and amyloid β first build up in the hippocampus, causing memory loss. In a similar way, Lewy Bodies form in the substantia nigra, where they destroy dopamine signalling neurones required for controlling movement.

That’s a brief overview of Parkinson’s disease (aren’t my blog posts up beat?!), but what I really want to talk to you about is an interesting link between these two neurodegenerative diseases. In a surprising number of dementia cases, signs that are normally associated with Parkinson’s disease have been found. The presence of α-synuclein appears to occur alongside tau. Not only this, but it appears that the two proteins somehow interact to cause a more severe form of the disease. Structures in the brain are damaged more when both of the misfolded proteins are present. But, as per usual, this is about all that is known. There are some theories about how α-synuclein causes an increase in tau’s affects:
Tau normally helps to ‘stabilise’ structures called microtubules in our neurones. These microtubules act like trains to transport goods from one end of the cell to the other. In Alzheimer’s, the tau can no longer do this because of modifications to its structure, in part caused by a particular enzyme. A possible theory is that when α-synuclein is present, it activates this enzyme into further modifying tau, causing the ‘trains’ in our cells to stop transporting. As you might expect, if proteins aren’t reaching the areas of the cell where they are needed, there is going to be a nasty knock-on effect on how the neurone will function.

A project in our lab has recently shown that over-expressing both tau and α-synuclein in flies (poor flies) causes a larger change in the animal’s behaviour. Casey Morris, a PhD student in our lab, spent her undergrad project creating genetically modified cell lines expressing both Alzheimer’s related and Parkinson’s related proteins. The flies were put through all sorts of experiments to determine changes in their behaviour. Over 3 months, she monitored the flies and was able to calculate any differences in their average life span. She found that when both tau and α-synuclein were expressed in the brain, the life span of the flies was significantly decreased compared to when just tau was expressed. She also used a technique to monitor the climbing ability of the flies. If you tap a fly to the bottom of a tube, it pretty quickly runs back up. With age and in disease, this climbing ability decreases. When the two proteins acted together, the fly’s climbing ability decreased at a faster rate than with just tau alone.
These simple behavioural studies prove that when the protein normally associated with Parkinson’s disease is also present in the brain of someone with Alzheimer’s Disease (or some tested animals at least), causes more dramatic effects.

Parkinson’s like symptoms have been linked to Alzheimer’s disease and this mixed bunch of disrupted protein might provide a reason why. There has also been some cases where tau has accumulated in the neurons affected in Parkinson’s disease (in the substantia nigra), possibly another reason for the overlapping symptoms.

More work is needed to determine exactly how this worsening of symptoms is caused. The link leads us to interesting questions within the field of neurodegeneration. If you have a neurodegenerative disease, are you more prone to develop another? Are certain brains generally more susceptible to neurodegenerative disease or are they just unlucky random occurrences?

References

Substantia Nigra in Alzheimer’s disease: Burns, J., Galvin, J., Roe, C., Morris, J. and McKeel, D. (2005). The pathology of the substantia nigra in Alzheimer disease with extrapyramidal signs. Neurology, 64(8), pp.1397-1403.

α-synuclein in Alzheimer’s: Arai, Y., Yamazaki, M., Mori, O., Muramatsu, H., Asano, G. and Katayama, Y. (2001). α-Synuclein-positive structures in cases with sporadic Alzheimer’s disease: morphology and its relationship to tau aggregation. Brain Research, 888(2), pp.287-296.

Casey Morris PhD student, University of Southampton

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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?

image
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!

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:

 

Flying Around

When I tell people about the research we’re doing in my lab, everyone’s first question is always how do you give flies Alzheimer’s disease? Followed by how can you find out anything useful from a fly? They’re both valid questions which I didn’t understand for a long time, so I’ll try and briefly explain the answers here.

The answer to the first question – how do you give flies Alzheimer’s disease – is that actually, you can’t. There is no one cause of Alzheimer’s disease. It appears to be caused by multiple cell mishaps which I’ll talk about in another post. This complexity and the fact it isn’t completely understood means you can’t replicate the full disease in any model. But you can replicate certain features. By over-expressing or under-expressing certain genes in the fly, you can induce changes in the ‘phenotype’ i.e.- a behavioural or physiological change (or both). Not only that, it is also possible to express human versions of genes (in true ‘Cramps’ style) in the fly to give a more accurate depiction of what happens in the human disease.

You don’t often associate flies as having behavioural traits like learning and memory, but actually they do. Flies are capable of long term and short term memory which has found to be altered with age, just like in humans. Now obviously, humans have a much more sophisticated and complex neuroanatomy to allow more complex memories, but the underlying basic circuitry in the brain is very similar between us and the flies. This means we can train them to remember and we can track differences in the animals with Alzheimer’s like symptoms. We can use cheap and simple experiments to measure these behaviours. For example, my work uses an experiment where we teach the flies to evade their normal response to go towards light. We can train them to associate light with a chemical called quinine which they don’t like the taste of. Later on, we can then assess whether they have remembered to associate light with something they would normally avoid.

There are many other behavioural experiments to examine changes in flies with different genotypes, but there is also biochemical data that can be found. For example, you can look at fly brains under the microscope and image certain neuronal tracts using fluorescent staining. This is a pretty cool technique and lets you see changes that occur to neurons in Alzheimer’s brains. Not only this, but you can also use live larvae to image axonal transport (transport of molecules up and down neurones). Because fly larvae have clear cuticles, you can see right into their bodies and when a fluorescent dye is added, you can actually video the neurones doing their thing!

Now you may still be wondering why you would choose a fly to do these assays, but there is a very straight forward answer – flies are cheap and much easier to look after. Plus you can get very convincing results with a large number of flies very quickly. A fly also has a maximum lifespan of about 3 months meaning that experiments involved in ageing (a very important factor in Alzheimer’s research) can be done easily. A mouse, for example, has a lifespan of a couple of years so ageing experiments are much harder and more expensive.

So yeah, flies are pretty good for lots of reasons. Just not when they eat your fruit.