This proposal is built around the investigator's finding that presenilin 1 interacts with members of the Armadillo family. One interactor is beta-catenin (designated Armadillo in Drosophila), a protein with dual roles: it is a component of the adherens junction, an adhesive structure which forms between homotypic cells, and an intermediary in the Wingless/Wnt signaling pathway which is involved in body axis formation and segment polarity. The second interactor discovered is a novel member of the same family designated delta-catenin. Like beta-catenin, this protein also contains a series of 42 amino acid imperfect repeats and is resident in the adherens junction. The connection to Wingless/Wnt signaling provides another facet to previous observations that genetically linked presenilin to Notch; both of these pathways utilize Disheveled as an intermediary. The investigators have assembled preliminary data from highly independent directions that converge on the idea that presenilin 1 and its interactors play a fundamental role in neuronal cell adhesion, particularly during development of the nervous system. Concordant with this idea is our finding that delta-catenin is the only neuron-specific member of the Armadillo family. In the mature nervous system, many of these same molecules may be involved in the establishment and maintenance of synapses. The identification of genes which function in concert with presenilin provides an opportunity to manipulate these functional systems in ways that will alter the known effects of presenilin on amyloid precursor protein (APP) processing. Many investigators agree that presenilin alters the specific cleavage of APP leading to AB. By delivering upstream signals to cells that will alter the stability of the presenilin interactor, beta-catenin, they can alter levels of AB. The cleavage event termed gamma-secretase involves an enzyme activity within the hydrophobic environment of the membrane and they have directed efforts toward the effects of signaling on Abeta generation within a specialized lipid environment.
The specific aims are designed to precisely define the interactions already described, to assign a specific cellular locus for delta-catenin in the mature nervous system as well as to further pinpoint its role in the developing nervous system, and finally to use the assembled data as a lead in discovering novel regulatory approaches to the generation of Abeta.
