Munich: New target for Alzheimer’s Disease

Research lead

The brains of Alzheimer patients have high accumulations of the material beta-amyloid, which appear in the form of plaques. The precursors of these plaques are believed to be the underlying cause of the nerve cell loss that leads to the disruptions in memory that characterise Alzheimer’s disease.

The main aim of many Alzheimer therapies is therefore to inhibit the formation of beta-amyloid. Since beta-amyloid is cleaved from the so-called amyloid precursor protein (APP), scientists have focused on stopping the two enzymes that attack the precursor protein. These act like molecular scissors and cut out the beta-amyloid fragment. Blocking these scissors precludes the formation of beta-amyloid.

Now, German researchers have succeeded in identifying an enzyme, alpha secretase, which cleaves (APP) without forming beta-amyloid. Up to this point three different candidates for this function had been under consideration, but the research team has now been able to show that the enzyme ADAM10 (A Disintegrin And Metallopeptidase 10) is solely responsible for the specific cleavage.

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 RNA interference, the researchers blocked each of the three candidate genes thought to code for the ADAM enzymes. An analysis of the cleavage products revealed that the ADAM10 gene was the only one able to prevent the formation of beta-amyloids. The results were confirmed 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,” says 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,” says Lichtenthaler.

The antibodies could be used to measure ADAM10 activity in spinal fluid and, by extension, identify people who may have an increased risk of developing Alzheimer's disease.