This is the second competing renewal of our Program Project Grant (PPG), entitled, "Signal Transduction and Alzheimer's Disease". This PPG was developed from a program established in the Laboratory of Molecular and Cellular Neuroscience in 1990 for the purpose of investigating the biochemistry, cell biology, molecular biology, and pharmacology of regulation, by protein phosphorylation, of the Alzheimer amyloid precursor protein (APP). Studies of the cellular and molecular mechanisms underlying the sequential cleavage of the APP to [unreadable]-amyloid (A[unreadable]) by [unreadable]-and ?-secretases have afforded great insight into the etiology of Alzheimer's Disease (AD).Understanding the mechanisms that regulate A[unreadable] generation may enable the development of pharmacologically active compounds that target A[unreadable] formation. A group of experts in various disciplines of biomedical research will carry out these studies using distinct but complementary approaches. Project 1, entitled "Effects of A[unreadable] on Synaptic Structure, Transmission and Plasticity", will investigate the effects of A[unreadable] on dendritic spine morphology, glutamate receptor trafficking, and long term potentiation in cellular and mouse models of AD. Project 2, entitled "Mechanisms of ?-Secretase Regulation" will characterize the underlying mechanism(s) by which ATP, and ATP analogs, including Gleevec, regulate [unreadable]APP processing and trafficking. Project 3, entitled "Role of CK1 in Alzheimer Disease Etiology" will evaluate the role of the protein kinase, CK1, in [unreadable]APP processing, and identify the targets for CK1 involved in this process. These studies will be supported by a Scientific Core (Core B) that will produce key materials and perform routine, yet critical, tasks that will be required to accomplish the studies described in the other Projects. An Administrative Core (Core A) will coordinate various aspects of the PPG, integrating day-to-day activities of the investigators and consultants involved in the various projects. These studies will lead to greater knowledge of mechanisms involved in the production of A[unreadable] in the brains of AD patients and will hopefully identify novel proteins that can be targeted by therapeutic agents. REVIEW OF INDIVDUAL COMPONENTS CORE A - ADMINISTRATIVE CORE;Dr. Paul Greengard (CL) DESCRIPTION (provided by applicant): The objective of the NIA Program Project funding mechanism is to provide for greater opportunities and capabilities through the unification of a shared commitment to a central investigative theme. The main goal of the Administrative Core is to facilitate and support the unification and interaction of the scientists and administrative personnel working on the Proposal at The Rockefeller University, Weill College of Cornell University and Yale University School of Medicine. Specific Aims: Aim I. Coordination of and communication among between the Cores and Projects in the Proposal - Facilitate communication between the three Projects and two Cores, the scientific and administrative staffs at Rockefeller, Cornell and Yale and consultants from other institutions - Schedule and coordinate all formal meetings - Facilitate the transfer of information for data sharing and manuscript generation - Career development coordination center for students and postdoctoral trainees Aim II. Maintenance of the Physical Working Space, Supplies and Equipment for the Proposal - Maintenance of the physical laboratory and administrative space - Oversight of the laboratory safety guidelines - Purchase and maintenance of supply stocks Aim III. Data and Progress Record Maintenance and Clerical Support for the Proposal - Clerical support and record maintenance - Maintenance of project-generated resources files - Publication generation and archive - Supply and equipment record maintenance - Budget tracking and allocation for the Cores and Projects - Data sharing of biological material resources and tools generated by the NIA Program Project Grant