Researchers target Alzheimer's enzyme
Alzheimer's disease was made as scientists targeted an enzyme,
which has a differentiated role and opens up perspectives for new
drugs that have fewer undesired side effects.
Alzheimer's disease, a degenerative disease that gradually and progressively destroys brain cells, affects between 50 per cent and 70 per cent of all cases of dementia and is therefore the major form of dementia.
Alzheimer's disease involves a kind of plaque that forms in the brain cells. A major role in this process is played by gamma-secretase, an enzyme that cuts proteins in a particular place. Sometimes the gamma-secretase cleavage goes wrong, causing the creation of a by-product that sticks together and precipitates thus forming the plaque.
Scientists from the Flanders Interuniversity Institute for Biotechnology (VIB), investigated this key role of gamma-secretase to try to find substances that were able to block the formation of plaques.
Gamma-secretase is divided into several entities, but until now scientists have assumed that the complex acts as a homogeneous unit. The researchers showed that gamma-secretase's various sub-units exhibit very diverse, tissue-specific activity. They concluded this from research in which they inactivated one or more sub-units in mice.
The effect of this inactivation turns out to be very specific for each sub-unit. In one instance, the mice embryos were not viable but the inactivation of another sub-unit led to adult mice in which the activity of gamma-secretase was significantly reduced.
This opens up new possibilities for the development of medicines that focus on the inactivation of gamma-secretase. Current methods prevent the action of the entire complex, they also cause a lot of undesired side effects. The findings of the researchers make it possible to develop drug treatments that are targeted on a single sub-unit and thereby have a much more specific action.
"You will probably never be able to give people their memory back," commented Bart De Strooper, lead researcher of the study.
"So, the main purpose of a medicine will be to salvage as many brain cells as you can by halting the progress of the disease in the areas of the brain where it has already developed, and by preventing plaque from forming in the parts of the brain they have not yet affected."
There are an estimated 18 million people in the world with dementia, according to the charity Alzheimer's Disease International, which estimates that by 2025 this figure could increase to 34 million.
With anticipated increases in the future to the number of sufferers, considerable research is in progress to understand the pathomechanism of the disease and find a cure. While sufferers show improvements when taking acetylcholinesterase inhibitors, their mechanism of action does not correct the basic pathology of the disease, the beta amyloid deposits or neurofibrillary tangles that are characteristic of the disease.
The only current approved neuroprotective therapy in Europe is memantine( Namenda, Axura), which is already approved in the US and has been for some time. Neuroprotection is seen as a better alternative to acetylcholinesterase inhibitors, which treat the symptoms of the disease and are the most viable form of treatment currently available.
With increasing patient numbers and the limitations of available therapies, the Alzheimer's disease (AD) market is an attractive investment with huge unmet need. Although it occupies a small share of the total CNS market it is currently experiencing massive growth. Alzheimer's disease market in the seven major markets is worth $4.7 billion (€3.8 billion) and will increase to $6.1 billion by the year 2005 and $ 7.8 billion by the year 2010.
The research of the VIB scientists from Bart De Strooper's group appears on 1 February in the journal Proceedings of the National Academy of Sciences.
