The precursors of the high accumulations of the beta-amyloid - appearing in the form of plaques - in the brains of Alzheimer's patients are thought to be the underlying cause of the nerve cell loss that leads to Alzheimer's. Now scientists have identified an enzyme, alpha secretase, which cleaves the amyloid precursor protein (APP) without forming beta-amyloid.
The work, by researchers at the German Centre for Neurodegenerative Diseases (DZNE) and Ludwig Maximilian University of Munich (LMU), appears in EMBO Journal.
The research team has now been able to show that the enzyme ADAM10 alone is responsible for the specific cleavage. Dr. Stefan Lichtenthaler and his team developed highly specific antibodies that can identify the different cleavage products of the precursor protein in the brain cells of mice and in human cell cultures.
Using a special technique called RNA interference, the researchers managed to block each of the three genes that code for the three ADAM enzymes under suspicion. An analysis of the cleavage products revealed that the ADAM10 gene was the only one able to prevent the formation of beta-amyloids. They confirmed their results using mass spectrometry.
"In ADAM10 we have identified a target molecule that plays a central role in the development of the molecular processes in Alzheimer's disease. We know that ADAM10 is less active in Alzheimer patients," said Dr. Lichtenthaler. When ADAM10 is less active, the precursor protein is more likely to be cleaved in a way that promotes the formation of beta-amyloids.
"It is possible that less ADAM10 activity could increase susceptibility to Alzheimer's disease. If that is the case, stimulating ADAM10 could be an important mechanism for therapy. But our antibodies also open up new possibilities for diagnosing and preventing the disease," said Lichtenthaler.
The antibodies could be used to measure ADAM10 activity in spinal fluid and, by extension, identify persons who may have an increased risk of developing Alzheimer's disease. A series of experiments to examine this possibility is already underway.