BACKGROUND:

OMRF’S BREAKTHROUGH DISCOVERY ON ALZHEIMER’S DISEASE

February 14, 2000

WHAT IS ALZHEIMER'S?

Alzheimer’s disease, named for German psychiatrist Alois Alzheimer in 1906, is a neurological disease characterized by a progressive decline in memory, judgement, and the ability to reason and sustain intellectual function.

Early symptoms include memory loss, difficulty with abstract thinking, and disorientation. As the disease progresses, behavioral and personality changes occur. Complications related to Alzheimer’s usually result in death between 2 – 10 years of onset.

WHY DOES ALZHEIMER’S OCCUR?

While doctors diagnose "probable Alzheimer’s disease" by ruling out other similar conditions, an official diagnosis can only be made upon autopsy. Doctors and scientists have determined that lesions present in Alzheimer’s patients’ brains are responsible for the neurological disease.

These lesions are now commonly referred to as "plaques and tangles." In the 1980s, scientists discovered that the plaques were made primarily of the deposit of a small protein called beta amyloid (A-beta). In Alzheimer’s patients, A-beta does not dissolve, as it does in healthy persons, but instead accumulates into fibrils, which stick together to form the plaques. Therefore, the problem in Alzheimer’s patients is not the presence of A-beta, but rather having too much of the substance or the inability to dispose of it normally. The plaques and tangles caused by A-beta disrupt brain function by killing neurons, or brain cells. As brain cells die, they cannot be replaced, unlike other cells in the body, and symptoms of Alzheimer’s become evident. As more neurons die, the brain cannot signal the body to conduct basic functions, eventually causing the body to shut down completely. This makes the questions "where does A-beta come from and how do we get rid of it" very important if we are to understand and treat Alzheimer’s disease.

Shortly after the beta amyloid determination, scientists discovered that A-beta was a part of a larger protein called amyloid precursor protein (APP). APP is present in all people and it is normally cut up by proteases, which are the enzymes our body uses to cut proteins. Scientists thought that there must be two proteases affecting APP, and these enzymes were dubbed as "beta-secretase" and "gamma-secretase." Each cuts APP at a specific place and as a result, A-beta is released between the cuts. These findings make beta- and gamma-secretases important to Alzheimer’s research. If we can recognize these enzymes and find a way to block them, we will likely stop the progression of Alzheimer’s disease. For many years, scientists have been looking for these proteases, but have not found them until now. (figures1, 2 & 3)

HOW DOES THE RECENT OMRF DISCOVERY AFFECT ALZHEIMER’S?

OMRF scientists have been engaged in research on Alzheimer’s disease for over 15 years. In the 1980s, Dr. Robert Floyd devised anti-inflammatory chemicals to ease the degeneration of an Alzheimer’s brain. Recently, a team of scientists in the Protein Studies Program, led by Dr. Jordan Tang, discovered the identity of the long sought beta-secretase and have given it the name "memapsin 2." Memapsin 2 was shown to cut APP in test tubes and in live cells at the precise place known for the beta-secretase cut. Moreover, memapsin 2 cut APP from certain genetic-linked Alzheimer’s patients faster than normal APP. These findings prove that this important protease has finally been identified. This new discovery is to be reported by Dr. Tang’s team in the Feb. 15 issue of the Proceedings of the National Academy of Science, USA.

Memapsin 2 turned out to be a kind of protease, called aspartic protease, for which Dr. Tang’s group has received international recognition for its important contributions through the years. In fact, the pioneering discovery of the first inhibitor for this kind of protease was done first by Dr. Tang’s laboratory in the 1970s. The principles discovered later were successfully applied to the making of successful inhibitor drugs to stop HIV in AIDS patients. Now, scientists are optimistic that this same kind of principle will be applied to create inhibitor drugs which will stop memapsin 2 and the progression of Alzheimer’s disease.

Since it is difficult to study memapsin 2 when it is still inside of human brain, one of the most important aspects of this discovery was the ability to "express," or reproduce, a significant amount of the enzyme for additional research purposes. In doing so, Dr. Tang and his team were able to study memapsin 2 in greater more detail. Scientists from other laboratories around the country have also identified the beta-secretase gene, but have been unable to learn how this enzyme works with the level of detail as in Dr. Tang’s work. Obtaining this basic information is important for the design and testing of inhibitor drugs. For example, Dr. Tang’s group has determined the structures that are preferred for the recognition of the memapsin 2 active site; that is, the site where the cutting takes place. This is important information for inhibitor drug design.

WHY IS THIS NEW DISCOVERY SIGNIFICANT?

The identification of memapsin 2 by OMRF scientists offers great insight into Alzheimer’s disease. The new information on this protease offers a better possibility for inhibitor drug design. If we can prohibit the build-up of the A-beta by blocking memapsin 2 with inhibitor drugs, we should be able to stop or limit the progression of Alzheimer’s disease. By pinpointing the genesis of Alzheimer’s disease, scientists will now be able to develop a method to appropriately address the nature and control of the disease. If memapsin 2 inhibitor drugs are proven to be effective in treating Alzheimer’s, new medical technology will likely to be developed for the detection of the disease before its onset. The discovery also offers new hope that someday in the not too distant future, Alzheimer’s will become a manageable disease, like diabetes or high blood pressure, instead of the hopeless and helpless situation patients and their families face today.

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Alzheimer's Breakthrough