The Journal of Quality Research in Dementia Issue 8 (lay version)

What have fruit fly models of Alzheimer's disease ever done for us?

Fruit flies seem like an unlikely scientific hero, but researchers have greatly improved their understanding of diseases such as Alzheimer's and Parkinson's thanks to information gleaned from the humble Drosophila.

How can such a simple organism as a fruit fly help us to understand such a complex disease as Alzheimer's that affects creatures as sophisticated as human beings?Fruit fly

Animal models

Researchers use animals to create models of diseases or injuries that affect humans. This allows them to investigate the condition in a way that would be impossible to do in a person. It is important that the mechanism that causes the disease in the model animal is similar to the mechanism in humans.

A model model

Fruit flies have a very short life cycle compared to other animals, such as rodents, that are often used to develop models of disease They live for two to three months, which makes it very easy to see the effects of experiments over the fly's whole life span. This is invaluable for investigating neurodegenerative diseases such as Alzheimer's disease, which only develop in old age.

They are also a cost effective option; fruit flies breed rapidly and are inexpensive to keep. This means that it is easy to conduct relatively large scale experiments using Drosophila.

But can such practicalities make up for the fact that human beings are very different to fruit flies? Surprisingly when it comes to the mechanisms that are involved in Alzheimer's disease there are many similarities between Drosophila and ourselves. Researchers know a lot about the genetics of fruit flies as they have been studying them for over a hundred years. In fact around 60% of genes in the fly are the same as in humans.

On top of these similarities it's possible to create what is known as a transgenic model of Alzheimer's disease by introducing human genes linked to the condition directly into the fly. The fruit fly's long-established popularity as a model for investigating genes means that researchers have developed large numbers of tools and tests that we know can measure and monitor what is going on in their biology. This means that researchers are able to study the behaviour of individual genes and how they interact with the rest of the processes and mechanisms that exist within the fly. By tinkering with the genes in fruit flies and observing the outcomes, scientists can improve their understanding of what role those mechanisms play in human biology.

The fly's simplicity means it is easy to screen the entire organism rather than having to focus on specific areas and potentially miss interactions. It is also possible to use "marker" genes to track inheritance of a gene through successive generations.

Because fruit fly maggots have transparent skins, it is also possible to use fluorescent chemicals to tag particular interactions or processes. This enables researchers to clearly identify and observe the processes taking place within nerve cells.

Drosophila and Alzheimer's disease

Tau is the name of a protein that is usually found in the longest part of our nerve cells, called the axon. This protein plays an important role in maintaining the structural health of brain cells as well as their ability to communicate with each other. However tau is also the main component of the neurofibrillary tangles that are found, along with amyloid plaques, in the brains of people who have Alzheimer's disease. Neurofibrillary tangles consist of bundles of pairs of tau proteins that have formed long strands and then become twisted up together inside a neuron. They distort the cell and mess up its internal machinery, eventually filling up all of the space in the cell so that it "chokes" to death.

For the last ten years fruit flies have been used as a model to explore what is going wrong with tau in Alzheimer's disease. Researchers have also used flies to identify possible treatments that can correct this source of damage.

Lessons learnt

The first study showed that when abnormal human tau was present in the nerve cells of fruit fly maggots it led to the degeneration and damage of the cells in a way similar to that seen in Alzheimer's disease. Further studies showed that flies that developed this version of Alzheimer's disease developed a clearly identified pattern of damage in their eyes. This made them easy to spot, which in turn made it easy to identify when drugs or genetic manipulation had helped to prevent or reverse the condition. Being able to carry out large-scale trials of potential treatments at this level has enabled researchers to identify a number of drugs or molecules worth further investigation as potential treatments.

Further experiments have been carried out to explore how abnormal tau proteins affect nerve cells before they develop tangles and kill the cell.

Tau's normal function is to stabilize connection pipes, called microtubules, within the cell and to help form the cell's skeleton. The microtubules act as tracks for essential chemicals to be transported from one part of the cell to another. This axonal transportation system is how nerve cells communicate with each other. The theory being tested was that abnormal tau disrupted this transportation system, causing a breakdown in communication between cells and damage to their structure. This damage could explain the clinical symptoms of Alzheimer's disease at a point before the tangles are properly formed and the cell has died.

The fruit fly maggots that were used to test this theory had abnormal human tau in their nerve cells, but also a fluorescent tag in some of the cargo that was being transported along the axon in those nerve cells. When the abnormal human tau was present the cargo could not be transported to the synapse (the point of communication with the next cell) and so the nerve cells could not do the job they needed to do, which in this case was to communicate with muscles in the maggot. The larvae being used developed clear problems with their ability to crawl. Using fruit fly maggots in this way showed that what has become known as the 'tau and tangle' hypothesis is correct. Abnormal tau proteins significantly disrupt the function of nerve cells, even before tangles develop and nerve cells die.

The researchers went on to use this fruit fly model of how tau damages brain cells in Alzheimer's disease to screen potential treatments for the condition. They tested compounds on the maggots to see if anything could prevent the negative effects of the abnormal tau. They found that treating the maggots with lithium chloride (a drug used to treat bipolar depression) helped the cells to overcome their problems with axonal transport and improved the crawling behaviour in the maggots. Further research has now shown that the cell's ability to communicate was hampered by the breakdown of the axonal tracks and that lithium chloride effectively prevents this breakdown.

There have now been many studies of fruit flies where abnormal tau proteins have been introduced into different nerve cells in the fly. These experiments have enabled researchers to pinpoint what it is about the tau that is causing the damage in Alzheimer's disease. It is something known as its phosphorylation state. Phosphorylation is a biological mechanism that changes the role or activity of a protein. It has been shown that excessively high levels of phosphorylation impair tau's ability to bind to the transportation tracks in the cell and do its job.

Fruit fly models have shed significant light on what appears to be happening in the human brain when people develop Alzheimer's disease. When tau becomes abnormally hyper-phosphorylated it disrupts the communication between cells (a possible cause of the early symptoms of the disease). As the disease progresses the abnormal tau continues to disrupt the communication processes within cells and starts to damage the cells themselves, developing into tangles that cause the cell death that might lay behind the symptoms of the later stages of the disease.

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