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A Fine Balance for Dementia Drugs

The transparent nature of the roundworm Caenorhabditis elegans makes it easy for scientists to study its cells. Credit: HoPo/Wikimedia Commons

The transparent nature of the roundworm Caenorhabditis elegans makes it easy for scientists to study its cells. Credit: HoPo/Wikimedia Commons

By Yee Lian Chew & Hannah Nicholas

Since too much or too little of a key protein expressed in the brain can accelerate brain ageing, drugs developed to regulate its levels face a fine balancing act.

Diseases of the ageing brain, such as Alzheimer's disease, are becoming increasingly common but the causes of these conditions are relatively unknown. We have studied brain ageing in a small transparent roundworm, and found that accelerated ageing stemmed from either too low or too high levels of a protein called tau. We think that a similar thing may be happening in people, so our findings could improve our understanding of what causes Alzheimer's disease.

Dementia is one of the most important diseases of the ageing brain, with one in four Australians above the age of 85 developing some form of dementia. This disease is characterised by progressive impairment of brain function, such as memory loss, confusion, changes in personality and the inability to perform everyday tasks.

As the human brain gets older it gradually begins to accumulate small physical changes that correlate with a loss of brain function. These changes are also observed in other animals. Our research has used the small nematode worm Caenorhabditis elegans as a model to study how the brain ages.

The Tau Gene Regulates Brain Ageing and Overall Lifespan

In humans, the most common type of dementia is Alzheimer’s disease. In this and similar dementias, a protein that is encoded by the tau gene appears to be strongly involved in disease progression. In fact, in the brains of people with Alzheimer’s disease, the tau protein forms large clumps called “tau tangles”. The formation of these tangles may be toxic to the brain. For this reason, we are very interested in what the tau gene is doing in the ageing brain.

One strategy to investigate the functions of tau in the brain is to study animals in which the gene product is mutated. The worm has a gene that is similar to human tau called “protein with tau-like repeats” (ptl-1). For simplicity we will refer to it here as tau.

Our laboratory has access to two tau mutant worm strains: one where the entire gene has been “knocked out” and another where the gene is truncated. These mutant strains were observed under a microscope for the main part of their adult life, or 15 days, to investigate how their brain cells were ageing. We would expect that the brain functions that are attributable to tau would be impaired in both the knockout mutant and the truncated mutant.

How can we tell how fast the worm brain is ageing? Brain cells accumulate small changes in their physical structure as they get older. In ageing worms, the brain cells develop branching and blebbing along nerve fibres called axons, as well as branching from the body of the cell from which the nerve fibres derive. We can record the timing of when we observe branching and blebbing as the worm gets older, and use these data to track how fast its brain is ageing.

In normal healthy worms, branching and blebbing can only be observed late in life. Interestingly, we saw that the brain cells in tau mutant worms started to show these markers of ageing in mid-adulthood, which was significantly faster than in non-mutant worms. This suggests that the loss of tau in worms resulted in faster ageing of their brains.

We also found that some brain functions were impaired at early adulthood in these tau mutants, such as the ability to respond to touch or in their responsiveness to chemical stimulation of muscle.

Furthermore, the brain cells of worms with more copies, and hence higher levels, of tau also appeared to age faster than normal worms – at a similar rate to the tau mutants. Therefore, an imbalance in the levels of tau protein – either too little or too much – seems to make brain cells age faster.

Surprisingly, we also found that the tau mutants lived for a shorter time compared with non-mutant worms. In fact, for the worms where tau was knocked out, the lifetime of these animals was only two-thirds that of non-mutant animals.

Similarly, worms that have higher levels of tau protein are also short-lived. This shows that tau is not only vital for ageing of the brain but also appears to be important in the regulation of lifespan.

What Does This Mean for Dementia Patients?

The observation of tau tangles in Alzheimer’s disease suggests that the tau protein accumulates in a toxic manner and somehow clumps together in a way that results in disease. Therefore, one of the strategies to treat Alzheimer’s disease is to target tau and reduce its levels, thus preventing the formation of tangles.

Our research confirms previous data showing that too much tau protein is detrimental for the brain. However, we also found that too little tau results in the acceleration of brain ageing.

This suggests that the levels of tau must be tightly balanced, and strategies to treat dementia by targeting this protein must be cautious not to reduce tau to levels that are too low.

The importance of human tau in dementia has been extensively studied in rodents, providing a great deal of biochemical knowledge about how this gene affects brain ageing. Now the worm is emerging as a fantastic tool to study similar genes, and its convenience as a laboratory model facilitates large-scale studies such as pharmacological drug screening.

Our research in the worm provides important information about the molecular changes in the ageing brain that could lead to disease. This is a small but significant step towards understanding more about diseases of the ageing brain and towards the ultimate goal of improving diagnostic tools and treatments for those suffering from dementia.

Yee Lian Chew is a PhD candidate at The University of Sydney’s School of Molecular Bioscience, where Hannah Nicholas is a lecturer. This research was conducted in collaboration with Professor Jürgen Götz of the Queensland Brain Institute, The University of Queensland.

Box: The Worm as a Model to Study the Brain

Why is the worm useful to study brain ageing? Firstly, it has only 302 brain cells, making its nervous system far less complex and hence much easier to study than the human brain, which consists of billions and billions of cells. While worms and humans may look very different, at a cellular and molecular level they are surprisingly similar.

Secondly, the worm is transparent, making it very convenient to observe its cells under a light microscope. In addition, the worm has a relatively short lifespan of 3 weeks, so studies of ageing do not take too long to complete.

Taken together, the worm is an excellent model to study brain cells in a living, ageing animal over the course of its life.