Two Proteins Involved in Alzheimer's Disease

Two recently discovered proteins, aph-1 and pen-2, have been shown to play a role in the production of beta-amyloid, the main constituent of senile plaques associated with Alzheimer's disease. The two proteins are required for the activity of a third protein, presenilin, a key component of gamma-secretase, one of the two proteases responsible for the production of beta-amyloid. A report on the discovery was published in the July 2002 issue of Developmental Cell.

The study resulted from a joint project conducted by researchers from Exelixis, Inc. (San Francisco, CA, USA) and Pharmacia Corp. (Peapack, NJ, USA).

The research effort relied in part on Exelixis' expertise in using comparative genetics, functional genomics, and model systems to carry out a series of genetic screens in worms (C elegans) to elucidate the biological pathways involved in beta-amyloid production. These screens were based on the Notch signaling pathway, since gamma-secretase is known to play a dual role in cleavage both of Notch receptors and of the beta-amyloid precursor protein, betaAPP. Through systematic mutation and observation of the resultant phenotypic changes, the essential, conserved role of aph-1 and pen-2 in gamma-secretase activity was identified. Confirmation studies were performed in Drosophila and by demonstrating that the human orthologs of aph-1 and pen-2 were functional in the C elegans signaling context.

"The discovery of these two critically important proteins demonstrates the specificity of Exelixis' proprietary model system platform to discover novel gene targets that could have significant preventive and therapeutic potential against debilitating neurological diseases,” said Dr. George A. Scangos, president and CEO of Exelixis.