BioWorld International Correspondent

LONDON - The discovery of a molecule that might influence the development of Alzheimer's disease could open up new strategies for drugs to treat or even prevent it.

The molecule, called sorLA, reduces the risk of senile plaques forming in the brain, an international team of researchers suggested.

In Alzheimer's disease, a protein found in the membranes of neurons called amyloid precursor protein (APP) is broken down to form amyloid beta-peptide. The latter is the main component of the senile plaques that are typically found in the brains of people with Alzheimer's.

Work led by scientists at the Max Delbrueck Center for Molecular Medicine in Berlin has shown that sorLA helps to direct APP to a different, less harmful metabolic pathway.

Olav Andersen, postdoctoral scientist at the Max Delbrueck Center, told BioWorld International: "This paper is of great interest to people working on Alzheimer's disease because little is known about what APP actually does in the cell - and how it does it. Our research clearly shows that sorLA influences the life of APP, and suggests that a decreased level of sorLA could indeed be a cause of Alzheimer's disease."

The study is reported in the Sept. 7, 2005, issue of Proceedings of the National Academy of Sciences in a paper titled "Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein."

SorLA is a protein expressed in neurons. Until now, little has been known about its function. It belongs to a family of neuronal receptors, many of which have a role in "sorting" proteins - in other words, directing them to particular compartments of the cell once they have been manufactured in the nucleus, which is crucial for their correct function.

Research by others previously had shown that people with Alzheimer's disease had lower levels of sorLA than normal. Andersen, working in the laboratory of Thomas Willnow, together with collaborators in Australia, Denmark and the U.S., set out to discover whether those low levels of sorLA were a cause of the condition or rather a secondary effect of the disease.

They carried out a series of experiments to determine whether sorLA binds to APP, and whether sorLA regulates the processing of APP into amyloid beta-peptide.

The work showed that sorLA does bind to APP in nerve cells, thus preventing it from being broken down with resulting production of amyloid beta-peptide. Other studies demonstrated that genetically modified mice, which cannot produce sorLA, have increased levels of amyloid beta-peptide because the animals destroy APP at a much faster rate than wild-type animals.

Willnow and his team also looked at the brains of patients who had died from Alzheimer's disease, and compared them to the brains of controls who had not suffered from Alzheimer's. They found that the nerve cells of the Alzheimer's patients had not produced sorLA, but those of the controls had.

Writing in PNAS, the authors concluded: "Studies in vitro, in living cells, in knockout mouse models and in patients with Alzheimer's disease all support the concept that increased sorLA activity coincides with impaired APP processing and reduced amyloid beta-peptide production, whereas loss of receptor function promotes APP processing and amyloidogenic peptide formation."

SorLA, they wrote, appears to act as a kind of "sorting receptor" for APP that determines where APP goes in the cell and then what happens to it. "In particular, sorLA seems to confine APP to the Golgi and to impair its transition to the cell surface, a step that is crucial for conversion" into either amyloid beta-peptide or less harmful products.

They speculated that "levels of sorLA activity in individuals may affect the overall kinetics of APP transition and processing in a subtle way but act cumulatively over decades to determine plaque burden and spontaneous AD progression."

In the future, the team hopes to identify substances that could increase the production of sorLA in the brains of those people who produce insufficient amounts of the chemical. It might be possible, the researchers said, to reduce the formation of senile plaques in the brain by modulating sorLA levels.

Andersen said: "This could provide a new opportunity to cure Alzheimer's disease, or postpone its onset. It could also provide a way of screening for those who are likely to develop the condition. Some of our future work will involve looking at whether sorLA levels can predict who will develop the disease."

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