Neurobiology of Amyloid--interventional approaches

描述：（改编自应用程序） 在项目3中，研究人员使用了一些实验方法： 了解Mo/Hu-APPswe转基因（Tg）并可能引发疾病 在淀粉样蛋白沉积开始之前， 淀粉样蛋白沉积的严重程度。在第一种方法（具体目标1和2）中， 他们假设突变的APP对功能储备有不利影响， 脑胆碱能、肾上腺素能和去甲肾上腺素能系统的可塑性 重要的认知和记忆，这种效果解释了早期的 Mo/Hu-APPswe Tg小鼠的认知表现缺陷（早在 B-淀粉样蛋白[AB]沉积的开始）。为了证明缺陷， 可塑性，他们将挑战胆碱能和单胺能系统， 手术或神经毒性损伤或刺激它们对适当的 营养因子他们预测Mo/Hu-APPswe Tg小鼠中的这些系统将 显示出对损伤和营养刺激的反应性降低， 这是老年动物神经元的特征（“过早衰老”）。在第二 方法（具体目标3和4），他们的目标是影响的过程中， Mo/Hu-APPswe Tg小鼠脑中的淀粉样蛋白生成 为了加速/增强（即，通过小胶质细胞刺激， 脂多糖）或预防（即，通过促进非淀粉样蛋白生成 通过雌激素的APP处理）AB沉积。因为炎症和性 类固醇越来越被视为淀粉样蛋白生成相关的主要调节剂， 对于AD，具体目标3和4的研究成果可能具有重要意义。 临床意义在音乐会上，项目3利用了一些 干预措施，以发现/加速/改变与 Mo/Hu-APPswe体内突变。

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.