Synaptic damage in models of beta-amyloid associated pathology

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his new application is to request five years of support for an interdisciplinary investigation of hippocampal mechanisms mediating memory. Understanding these mechanisms is vital because their impairment appears to underlie the memory deficits seen in aging and in Alzheimer's disease. From rodents to humans, the hippocampus and adjacent interconnected structures are principally concerned with memory. While the anatomical connectivity within the subfields of the hippocampus is reasonably well delineated, how each of the subfields contribute to learning and memory functions are not clear. At the same time, neurons within the substructures are susceptible to damage and death following injury such as cerebral ischemia, in aging and in certain neurodegenerative diseases such as Alzheimer's disease. In particular, consistent presence of Alzheimer associated pathological lesions in this structure isolates the hippocampus from its cortical connectivity. Consequently, the selective vulnerability of this brain region is likely responsible for the cardinal manifestations of memory impairment in Alzheimer's disease. The working hypothesis that guides this program is that perturbations of axonal and synaptic compartments, either through structural or functional damage, lead to early synaptic dysfunction and result in learning and memory deficits in aging and neurodegeneration. This program will focus on the hippocampus proper, particularly the CA1 and CAS regions with two major goals in mind. First, we will examine the core learning and memory functions of these two subregions of the hippocampus using a novel, selective, and transient inactivation of these neurons through a combination of genetic and pharmacologic means. These manipulations will use exciting new technology developed at The Salk Institute and will allow us to reversibly probe the function of CA1 and CA3 subregions in learning and memory not previously possible. Second, we will investigate the mechanisms responsible for axonal and synaptic changes in this region, particularly in Alzheimer's disease related neurodegeneration. Specifically, we will examine cultured neurons and various mouse models to test several mechanisms that may contribute to hippocampal injury that are initiated by the amyloid beta-protein and the amyloid precursor protein. We propose that both amyloid precursor protein and various proteolytic products, including amyloid beta-protein, contribute in different ways to synaptic and axonal damage in Alzheimer's disease. By bringing together laboratories with unique expertise and background, we propose to probe the hippocampus in memory and in neurodegeneration by a multi-disciplinary approach. Further, a unique and key aspect of this Program is the sharing of common mouse strains, reagents, and vectors to facilitate the collaborative studies proposed in our four Projects.