application) The applications have generated two independent lines of transgenic (Tg) mice (lines C3-3 and El-2) that express mutant humanized amyloid precursor protein (APP) (Mo/Hu-APPswe) at levels sufficient to induce B-amyloid (AB) deposition between 20 and 24 months of age. These animals have been mated C57BL/6J mice for ten generations to obtain congenic animals (99.99%). In Project 1, they propose to conduct behavioral tests (Morris water maze, eight-arm radial maze, and Y-maze) designed to examine the cognitive abilities of their congenic/Tg Mo/Hu-APPswe mice. Following behavioral testing, each cohort (6-, 14-, 22- and 28 months of age) will be humanly sacrificed to provide tissues for detailed neuropathological/neurochemical evaluations (Project 2). Together, these studies will determine whether changes in cognitive performance correlate with specific neuropathological/ neurochemical abnormalities. The planned study will, for the first time, behaviorally characterize mutant APP Tg mice that are congenic on a single inbred strain background and will be the first to confirm findings of two independent lines of mice that express similar levels of mutant APP and develop AB deposits at similar ages. To explore the relationship between AB deposition and cognitive ability, they plan to mate Tg El-2 and C3-3 mice to each other to obtain double-Tg animals that will develop AB deposits and associated abnormalities at younger ages. These cohorts will be tested blindly and then sacrificed for neuropathological/neurochemical analysis (data provided by Project 2). Finally, a third line of Mo/Hu-APPswe mice (line Q2-2), which expresses the transgene at levels slightly less than required to induce AB deposition, will be behaviorally and neuropathologically/neurochemically analyzed. Their planned behavioral characterization of the mice, together with the neuropathological/neurochemical studies proposed in Project 2, will allow them to determine (with assistance in statistical analyses from Core B) the influence of APP hyper expression, AB peptide synthesis, and AB deposition on the cognitive abilities of mice.
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