Neurobiology of Amyloid--interventional approaches

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DESCRIPTION: (Adapted from the application) In Project 3, the investigators use a number of experimental approaches: to understand and possibly precipitate disease in Mo/Hu-APPswe transgenic (Tg) mice prior to the onset of amyloid deposition; and to influence the course and severity of amyloid deposition. In the first approach (Specific Aims 1 and 2), they hypothesize that mutant APP has adverse effects on the functional reserve (plasticity) of brain cholinergic, serotoninergic, and noradrenergic systems important for cognition and memory, and that this effect explains the early deficits in cognitive performance of Mo/Hu-APPswe Tg mice (well before the onset of B-amyloid protein [AB] deposits). To demonstrate deficits in plasticity, they will challenge cholinergic and monoaminergic systems with surgical or neurotoxic injury or provoke them to respond to appropriate trophic factors. They predict that these systems in Mo/Hu-APPswe Tg mice will show reduced responsiveness to lesions and trophic stimulation that is characteristic of neurons in aged animals ("premature aging"). In the second approach (Specific Aims 3 and 4), their goal is to influence the course of amyloidogenesis in the brains of Mo/Hu-APPswe Tg mice by employing strategies to accelerate/enhance (i.e., via microglial stimulation with lipopolysaccharides) or prevent (i.e., via facilitation of nonamyloidogenic APP processing by estrogens) AB deposition. Because inflammation and sex steroids are increasingly seen as major modifiers in amyloidogenesis related to AD, outcomes of research in Specific Aims 3 and 4 may have significant clinical implications. In concert, Project 3 utilizes a number of interventions to uncover/precipitate/modify disease associated with Mo/Hu-APPswe mutation in vivo.