Neurobiology of Amyloid--interventional approaches

描述：(改编自应用程序) 在项目3中，调查人员使用了一些实验方法： 了解和可能诱发Mo/Hu-APPswe转基因(Tg)中的病害 小鼠在淀粉样蛋白沉积开始之前；并影响病程和 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、5-羟色胺和去甲肾上腺素能系统的可塑性 对认知和记忆很重要，这种效应解释了早期 Mo/Hu-APPswe TG小鼠的认知操作缺陷(早在 B-淀粉样蛋白[AB]沉积的开始)。证明在…方面存在缺陷 可塑性，他们将挑战胆碱能和单胺能系统 外科手术或神经毒性损伤或刺激他们对适当的 营养因子。他们预测，在Mo/Hu-APPswe TG小鼠中，这些系统将 表现出对病变和营养刺激的反应性降低 老年动物神经元的特征(“早衰”)。在第二个 方法(具体目标3和4)，他们的目标是影响 Mo/HU-APPwE转基因小鼠脑内淀粉样蛋白的发生 加速/增强(即通过小胶质细胞刺激) 脂多糖)或预防(即，通过促进非淀粉样变性 雌激素对APP的加工)AB沉积。因为炎症和性行为 类固醇越来越多地被视为淀粉样变相关的主要调节剂 对于AD来说，在特定目标3和4中的研究结果可能具有重要意义 临床意义。同时，Project 3利用了许多 采取干预措施以发现/促成/修改与以下方面有关的疾病 体内Mo/Hu-APPswe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.