One of the major goals of our ADRC is to understand the biological substrates of mutant genes associated with impairments of cognition and memory. Project 2 takes advantage of the availability of several independent lines of mice (E1-2 and C3-3) expressing a chimeric Mo/Hu-APP-695 polypeptide that harbors the Swedish double mutation (KM 570-571 NL). These mice express the mutant APP (Mo/Hu-APPswe) at levels approximately threefold greater than endogenous mouse APP and, between 20 and24 months of age, develop Abeta42-immunoreactive deposits and associated cellular abnormalities. We have controlled for the homogeneity of genetic background by backcrossing our transgene array into C57/BL/6J mice for ten generations to obtain mice than are 99.99% congenic. Because our preliminary behavioral studies of Mo/Hu-APPswe Tg mice have documented the presence of mild memory deficits that antedate Abeta deposition, we hypothesize that shifts in levels of Abeta species, which occur significantly before Abeta deposition, are accompanied by subtle structural alterations in the neuropil (synaptic terminals/neurites) and that these lesions impact on behavioral performance. After the performance of these Tg mice is assessed in tasks of cognition/memory, animals will be sacrificed, and tissue swill be analyzed for regional changes in biochemical markers (e.g., levels of Abeta peptide species, synaptic proteins, neurotransmitters and their enzymes) an the character/severity of the cellular pathology (e.g., abnormalities in synapses, Abeta deposition, reductions in synapses, loss of subsets of neurons, evidence of cell death, activation of glial cells, etc.) in specific regions of brain. We believe that these clinical- neurochemical-pathological correlations will help to define the biological substrates of impairments in these mice, and this information will provide important insight into similar processes that occur in elderly humans, particularly in the preclinical and early stages of disease.