In the study, published recently in the journal JCI Insight, the researchers found two mutations in the gene endothelin-converting enzyme 2 (ECE2) which impaired its ability to break down amyloid beta protein. These mutations were present significantly more often in people with Alzheimer's than in controls--suggesting that the genetic variants in ECE2 could be causing, or at least contributing to, Alzheimer's symptoms.

The scientists looked at 741 people with late-onset Alzheimer's and compared them to controls. Unlike early-onset which affects people as young as 30, late-onset Alzheimer's is the most common form of this disease, generally affecting individuals after the age of 65.

The authors describe the identification of rare coding mutations in the endothelin-converting enzyme 2 (ECE2) gene in 1 late-onset AD family, and additional case-control cohort analysis indicates ECE2 variants associated with the risk of developing AD. The 2 mutations (R186C and F751S) located in the peptidase domain in the ECE2 protein were found to severely impair the enzymatic activity of ECE2 in Aβ degradation.

They further evaluated the effect of the R186C mutation in mutant APP–knockin mice. The team injected the mutated forms of the ECE2 gene into mice. They found mice with the mutation had increased levels of amyloid beta protein and plaque formation, and also exhibited some signs of Alzheimer's such as memory loss. When they expressed the wildtype form of the gene in the mice (i.e. the non-mutated form), amyloid beta protein levels decreased and the mice recovered some of their learning and memory deficits.

"These findings mean that ECE2 is a risk gene for people to develop Alzheimer's later in life," says the senior author. "Moving forward, we can try to target this gene and increase its expression as a way to treat Alzheimer's."

The researchers are now screening further for genetic mutations in a larger dataset as a way to validate these findings and to search for other variants in the ECE2 gene that could be contributing to Alzheimer's symptoms.

https://insight.jci.org/articles/view/135119

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fidentification-of_11&filter=22