In Vivo Identification of APP-Interacting Proteins

Project Summary

Alzheimer's disease is an incurable neurodegenerative disease characterized by the accumulation of amyloid plaques - deposits of protein in the brain whose main constituent is the Ab peptide, which is itself derived from the metabolism of a larger protein called APP. Reducing the Ab load in the brain is a major goal of Alzheimer's research, and to accomplish this, many strategies aim to inhibit the metabolism of APP. Thus, understanding which proteins APP interacts with is important because 1) this aids in the design of small molecule drugs, and 2) if APP metabolism is to be inhibited, an understanding of its natural function is critical. Although many studies have investigated the metabolism of APP in cultured cells, confirmation of these results in animal studies has not yet been achieved. Thus, we aim to generate a transgenic mouse that expresses APP containing a peptide tag. By using this tagged APP as'bait' in the living animal, we can subsequently purify it and those proteins with which it is bound. Analyzing the purified material and comparing it to a protein database will confirm binding partners identified by cell culture studies and identify new binding partners with new specific targets for drug therapy.