application): The use of transgenic animals to answer scientific questions is a powerful and informative approach that has been successfully undertaken by the core leader for more than five years to study neurodegenerative diseases. The purpose of the molecular biology/transgenic core is to extend production of existing transgenic mouse models of Alzheimer's disease (AD) to generate novel crosses between existing models, including mice showing endocytic pathway abnormalities or lysosomal system dysfunction, and to produce new transgenic models. The role of endosomal system abnormalities in A-beta production (project 1) will be examined in transgenic mice to be generated in this core, which reproduce the alterations seen in human sporadic AD, and in existing mouse models of human trisomy 21 (DS) showing early endocytic changes. In human AD, inheritance of the ApoE E4 exacerbates endosomal alterations, which will be further examined in mice expressing human ApoE epsilon 2 or 4 and in crosses of these mice with DS trisomic mice. Lysosomal system abnormalities seen in early AD are reproduced in the transgenic PS1 and PS1/APP mouse models originally created by the core leader. Project 2 will examine the direct relationship between activation of the lysosomal system and neurodegeneration in these existing models and by crossing PS1/APP mice with a cystatin B knockout mouse to further promote lysosomal system dysfunction. In collaboration with project 3, a transgenic mouse model that produces familial forms of cerebrovascular amyloid angiopathy (CAA), (the Flemish and Dutch APP mutation), will be created and used with an existing model of CAA available by collaboration to examine the cellular pathobiology common to both parenchymal and vascular damage in AD, and with project 1, to investigate vascular damage and its impact on A-beta uptake and/or clearance. The development of methods for in vivo imaging of chronic neurodegenerative diseases (project 4) will use existing models of beta-amyloid depositing mice as well as newly developed models of endosomal and lysosomal system dysfunction and CAA. The core leader has extensive experience managing large mouse colonies with complex breeding schemes and will be able to coordinate animal breeding, genotyping, and tracking of animals and their ultimate distribution to the project leaders in the most efficient manner. Overall, the inclusion of a transgenic core component to this application will greatly streamline the requirements for animal resources and strengthen the intellectual underpinnings that determine their use.
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