Enzyme Breaks Down Alzheimer's Protein
By Keith Mulvihill
NEW YORK (Reuters Health) - Japanese and American researchers reported on Thursday that a protein-dissolving enzyme in the brain may play a role in determining why some people develop Alzheimer's disease and others do not.
The enzyme, known as neprilysin, appears to be responsible for breaking down amyloid-beta, the stubborn snippets of protein that form clumps in the brains of people with the memory-robbing illness. The findings, from a study of genetically engineered mice, are published in the May 25th issue of the journal Science.
The researchers hope that the finding may one day lead to a treatment for the devastating disease and perhaps an early detection test for people who may have a family history of Alzheimer's disease. The enzyme may be one of several responsible for breaking down amyloid beta in the brain.
``Amyloid is like garbage in the brain and neprilysin is a garbage disposer. If the garbage disposer is not working in the aged brain as well as it used to, the garbage piles up and starts to destroy the brain function,'' said lead researcher Dr. Takaomi Saido of the RIKEN Brain Science Institute in Wako-shi, in an interview with Reuters Health.
``We believe this is likely to cause the majority of late-onset Alzheimer's disease and our study is the very first to give experimental basis for this assumption, identifying neprilysin as the major garbage disposer. Once we know the cause, we will be able to fight the disease by removing the cause,'' he added.
In the study, Saido and colleagues looked at mice genetically engineered to lack neprilysin. They found that when these mice were injected with amyloid protein, they did not break down the protein. The amyloid-beta also tended to accumulate in the brain in areas that tend to form plaques in Alzheimer's patients.
The researchers believe that any drop in neprilysin activity--possibly due to aging--my be one of the key steps in development of the disease.
They hope that drugs or even dietary compounds will be found that elevate or inhibit neprilysin activity, explained Saido.
``Therefore, we may be able to avoid having Alzheimer's simply by taking the former and avoiding the latter. A more positive approach would be a gene therapy to introduce neprilysin gene in the brain,'' said Saido.
``These approaches may even help to prevent familial Alzheimer's caused by gene mutations,'' he added.
Although such plaques are found in Alzheimer's patients, it has not been clear if they are a cause or a result of the illness.
In a second study, published in the same issue of Science, Dr. Ron R. Kopito of Stanford University in California found evidence that the protein clumps do indeed result in cell death and dementia seen in Alzheimer's, Parkinson's and other diseases.
In their study of cells, Kopito's team found that protein accumulation directly impairs an important cell system, known as the ubiquitin-proteasome system. Cells use this to regulate important functions, such as cell division, and also to purge abnormally folded proteins from the cell. The protein clumps seem to set up a vicious cycle, whereas abnormal proteins clog up the system, leading to an accumulation of even more protein.
``This is pretty basic study of the cell biology of protein aggregation. It provides a plausible model of how intracellular protein aggregation could be toxic to cells,'' Kopito told Reuters Health.
Such protein build-up is a prominent feature of nearly all neurodegenerative diseases, and the findings suggest that a loss of protein elimination function could be one way in which protein aggregates could contribute to cell death, explained Kopito.
``Much more basic work needs to be done before this can lead to any obvious treatment directions,'' he added.
SOURCE: Science 2001;292:1550-1555.
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