An ambitious EC-funded research initiative on epigenetics advancing towards systems biology

Duelling Dementia

August 2008

Marie-Laure Caparros describes the epigenetic mechanisms that can delay dementia.

Ronald Reagan had it. Charles Bronson had it. Charlton Heston had it. We're not talking about their mastery of cowboy gun fighting duels, but sadly Alzheimer's disease. For most people, the idea of losing their memory, their capacity to learn – and ultimately, their independence – is a total nightmare. The truth of the matter is that Alzheimer's disease and other forms of dementia are on the rise. In a population with an ever-increasing life expectancy, there is an inevitability that our bodies will succumb to degeneration, and the brain is no exception.

In an ageing population, an increase in the number of dementia cases is inevitable.

Borya

So, what do we mean by dementia? It's an umbrella term for diseases typified by brain cell degeneration beyond what is expected for a certain age group, due to damage or disease. Dementias that affect the cortex region of the brain – the outer region that is densely packed with nerve cells, or neurons – include Alzheimer's, and Creutzfeldt-Jakob Disease (CJD), the human equivalent of BSE. Memory loss and learning difficulties are the major consequences of these diseases. If we could look inside the brain, we would witness abnormal protein deposits, brain cells dying, and a reduction in new cell growth, which all contribute to brain circuit damage. Parkinson's and Huntingdon's disease affect the regions of the brain just below the outer cortex, and cause motor symptoms such as involuntary movements. So, how can we halt brain cell destruction? And how do we repair it?

There are no sure-shot drugs available

Ubi Desperare Nescio

Currently, there are no quick fix solutions. If we take Alzheimer's disease for example, the drugs on the market are less than satisfactory. Of the five commonly prescribed medications, the best patients might expect is a few more years of life. These drugs apparently enhance the function of the remaining neurons within their circuits: four of the five currently available slow the breaking down of the brain cell messenger chemical, acetylcholine. Acetylcholine keeps our bodies working normally, keeping us in touch with the world around us through our senses. It also controls our voluntary movements. The fifth medicine blocks a brain signal receptor called NMDA, which receives signals carried by another messenger chemical, glutamic acid, implicated in learning and memory. And at the clinical trial stage, it was recently reported that Rember, a drug that dissolves the tau protein tangles in the brain, is extremely promising at stopping cognitive decline. However, it is likely that it will be another five years before it is licensed for use.

In fact, there is evidence to show that taking good-old aspirin or Nurofen can help by keeping inflammation of neurons at bay. Inflammation can make cells dysfunctional or even tumourous. Taking these drugs long-term however, is not ideal given the increased risk of gastric bleeding and ulcer formation.

Keeping the mind active can help to defend against the onset of dementia

Michael Peterson

So what other therapeutic hope is there? One lifestyle factor is turning out to be very important in lowering the risk of developing Alzheimer's disease: life-long education. We have known for years that there is a link between education and dementia from population studies (Mortimer 1988). One particular piece of evidence has come from a Canadian team of researchers, who found that bilingual people were 5% less prone to developing dementia than people who couldn't speak a second language. Another very convincing case for the apparently reduced risk of developing dementia has come from environmental enrichment studies in animals.

Environmental enrichment keeps our animal friends active and happy in the zoo

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Environmental enrichment is used by zoo keepers to promote the welfare and quality of life for the animals they look after. This involves finding ways to stimulate both cognitive and physical activity, through games and puzzles. This is the best animal approximation we have for education in human subjects. Alena Savonenko and her research team at Johns Hopkins School of Medicine in Maryland used environmental enrichment to investigate the link between enhanced mental activity during puzzle solving, and improvements in dementia using mice with Alzheimer's disease. First, they tested a mouse's memory recall in a 'Morris' water maze, in which the mouse, keen to keep its head above water, has to navigate to find a submerged refuge platform. A second test investigated how shock can have an impact on memory: show a mouse an unusual object at the same time as making a loud noise, and it freezes in fright. If the mouse has an increased capacity for learning, subsequent exposure to the object is enough to provoke a fear response. Alzheimer's mice kept in enriched environments performed better in both memory tests, supporting the idea that cognitive stimulation slows decline due to Alzheimer's.

Like the tube in this model, DNA wraps around the histone protein bundles to form chromatin

Aaron Klug, MRC Laboratory of Molecular Biology, Cambridge UK

So what does this have to do with epigenetics? Li-Huei Tsai's team at the Massachusetts Institute of Technology found evidence that environmental enrichment could lead to a fundamental change in the brain cell's program – the instructions that describe how to make new cells. These changes are made to the actual shape of the packets of DNA in each cell, a modification to its epigenome.

To recap, changes that do not affect the DNA sequence are called epigenetic – they change the way DNA is wrapped up in the nucleus. DNA wraps around proteins called histones, like cotton around a spool, to make a package called chromatin. The characteristic features that change chromatin packaging are mostly chemical changes, either to the DNA itself, by the methylation of individual DNA bases; or to the histone packaging proteins they are wound around, by modifications such as acetylation, or methylation. These modifications can make regions of chromatin more tightly packaged, in which case the genes on the DNA in that region are silenced, or more open, which switches genes on. Tsai's team showed that environmental enrichment increases acetylation of the histone spools, which makes the chromatin package more open, activating a large number of genes.

So how does this decrease dementia risk? Both Savonenko's and Tsai's teams measured the apparent improvement in brain performance using several markers: the rate at which new brain cells are made; the number of newly-formed or re-established connections between cells; and the capacity of these connections to be conditioned for learning, termed 'synaptic plasticity'. What they found was that mice kept in environmentally enriched conditions had an increased brain mass, due to new cells being made. In addition, microscopic investigations revealed that the number of connections increased, while experiments using electrical signals in the brain demonstrated that synaptic plasticity became greater, with mouse subjects showing improved learning skills and memory recall.

Production of SirT1 enhances cognitive ability of Alzheimer's-affected mice

Public Library of Science

Having found out how education or so-called cognitive stimulation slows brain degeneration, the studies from Tsai's group bring hope of a drug therapy that could also help the process. They found that the epigenetic processes involved in Alzheimer's can be interrupted and reversed using a chemical called sodium butyrate. This drug blocks the enzyme that removes acetyl groups from the histone proteins within chromatin, leading to increased histone acetylation levels. The results of administering sodium butyrate showed an improvement in cognitive ability and memory recall in Alzheimer mice, that was about as effective as rearing mice in environmentally enriched conditions. Even better results came from the combined use of environmental enrichment and sodium butyrate.

Paradoxically, the most recent paper by Tsai's group discusses the beneficial effects of increasing acetyl group-removing enzyme. In theory, this would reduce histone acetylation. However, there are three distinct classes (each comprised of several types) of enzyme that carry out this task, and sodium butyrate only blocks two classes of them. The enzyme SirT1 belongs to a third class, and stimulation of its production improves the cognitive ability of Alzheimer's-affected mice. This enzyme is stimulated during famine or other stressful conditions and apparently activates pathways that delay aging. However, we do not yet fully understand how it works. One complicating issue is that SirT1 doesn't only work on histones, but also other proteins, including the p53 "guardian angel" protein that regulates a cell's life and stops it becoming cancerous. Because of this, we don't know whether the beneficial effects occur because of a decrease in histone acetylation, or some other reason not yet known. Whatever the mechanism, the results are promising. Many natural foods contain a SirT1 enhancing molecule called resveratrol, including red grapes, cranberries and Japanese knotweed. This molecule is currently being explored by pharmaceutical companies as a potential future medicine for Alzheimer's disease.

Research into Alzheimer's and other forms of dementia requires large-scale funding

Andrew O'Hara

The increase in the global number of cases of dementia is now being taken very seriously by the World Health Organisation (WHO). They have highlighted the fact that dementia is the third most onerous disease that healthcare systems face, and the fifth most common cause of death in the ageing population worldwide. Alzheimer's disease constitutes over 50% of dementia cases, amounting to almost 6 million sufferers in Europe alone. A huge part of the WHO's current campaign is to raise awareness of neurodegenerative diseases as being of important societal health concern. It is critical that more funding is allocated towards improving the treatment of these diseases. Hopefully, our growing understanding of the role that epigenetic modification has in Alzheimer's disease might offer a way to halt its debilitating consequences.