The overall goal of the Core project is to provide biochemical, pharmacological, and molecular biological support for the four component Projects of the proposed Program. Three Projects will focus on identification and development of chemical agents which influence the catabolic pathways of the amyloid precursor proteins (APPs). These studies will encompass the use of cell and tissue extracts (Project 1), intact transfected and normal cells (Project 2), and in vivo systems derived from normal (Project 2) and transgenic animals (Project 3). Projects proposed by two component groups will focus on cholinergic transmission. Project 3 will focus on defining the subtype(s) of the muscarinic acetylcholine receptor which are altered in aging and Alzheimer's disease, and the neuropeptide/modulator galanin will be studied in Project 4. A major function of the Core is to identify and obtain novel compounds from commercial sources and pharmaceutical companies for use by the component groups (particularly Projects 1 and 2, and in future years, also Project 3). These include inhibitors and stimulators of protein kinases and receptors; cation ionophores; ion channel blockers; lysosomotropic agents and agents which modify intracellular protein traffic. The Core will also serve as a liaison with industry in order to arrange for large-scale production and modification of any compounds that show desired properties. As an extension of its liaison activities, the Core will be responsible for organizing an annual meeting of an advisory committee composed of experts from academic laboratories with possible participation by selected representatives of the pharmaceutical industry. The Core will provide certain key reagents to various component projects. Projects 1 and 4 provide examples of these. Project 1 will be provided with purified holoAPP proteins and their fragments, overproduced using the baculovirus system. This will include site-directed mutagenesis, cell culture, protein purification, and microsequencing. The Core will provide peptide synthesis and recombinant DNA support to Project 4 for production of galanin analogs and galanin message associated peptide, GMAP.
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