Copper Complexing with Tetrathiomolybdate in a Murine Model of Alzheimers Disease

描述(由申请人提供)：本提案的目标是确定四硫钼酸铜的络合特性在阿尔茨海默病小鼠模型中是否具有足够的抗淀粉样蛋白或神经保护作用，从而证明该研究试剂的临床试验是合理的。 将使用阿尔茨海默病的Tg2576小鼠模型。一组小鼠将在阿尔茨海默病病理预防实验中进行研究，用四硫代钼酸盐在8个月时(斑块病理出现之前)开始治疗，一直持续到14个月大(斑块病理通常在未经治疗的动物中得到很好的证实)。第二组小鼠将在阿尔茨海默病病理治疗实验中进行研究，治疗从14个月开始，一直持续到16个月大。在每种情况下，Tg2576和野生型小鼠都将随机分为积极治疗组或仅使用药物组。野生型将被包括在内，作为行为和生化结果衡量的参考种群。 口服剂量是基于之前在小鼠身上进行的多项研究。在治疗期间，该剂量的有效性和安全性将通过血浆铜蓝蛋白水平进行监测，如有必要，将调整TM剂量，以优化铜的络合程度。还将通过跟踪小鼠的体重和每月进行常规运动测试(旋转杆、开阔场地测试)来监测安全性。在每个实验的治疗期结束时，将在Morris水迷宫中测试小鼠的空间记忆，作为淀粉样蛋白相关神经功能的指标。然后，将对小鼠实施安乐死，并收集脑组织，用于测定金属水平(铜、锌和钼)、β淀粉样蛋白、神经性营养不良、突触密度以及对脑蛋白的氧化和亚硝化损伤。 这一策略将实现以下具体目标：1)确定TM是否能预防淀粉样变性；2)确定TM是否能防止淀粉样蛋白相关的神经元损伤；3)确定TM是否能减弱已有的β淀粉样变性病变；以及4)确定TM是否能减轻已有的淀粉样变性神经细胞损伤。这些都是决定TM是否应该在预防或治疗阿尔茨海默病的临床试验中进行评估的关键信息。

DESCRIPTION (provided by applicant): The goal of this proposal is to determine if the copper-complexing properties of tetrathiomolybdate have sufficient anti-amyloid or neuroprotectant effects in a murine model of Alzheimer's disease to justify clinical trials with this investigational agent. The Tg2576 mouse model of Alzheimer's disease will be used. One cohort of mice will be studied in an Alzheimer pathology prevention experiment, with tetrathiomolybdate therapy initiated at 8 months (prior to the appearance of plaque pathology) and continued until the age of 14 months (when plaque pathology is typically well established in untreated animals). A second cohort of mice will be studied in an Alzheimer pathology treatment experiment, with treatment initiated at 14 months and continued until the age of 16 months. In each case, both Tg2576 and wild-type mice will randomized to active treatment or vehicle only. Wild-type will be included to serve as a reference population for behavioral and biochemical outcome measures. The oral dose is based on multiple previous studies in mice. The efficacy and safety of the dose will be monitored during the treatment period by plasma ceruloplasmin levels, with the TM dose adjusted if necessary to optimize the degree of copper complexing. Safety will also be monitored by following the weights of the mice and by performing routine motor testing (rotorod, open field testing) on a monthly basis. At the end of the treatment period in each experiment, the spatial memory of the mice will be tested in the Morris Water Maze, as an index of amyloid-associated neurologic function. Mice will then be euthanized and brain tissue harvested for determination of metal levels (copper, zinc, and molybdenum), beta amyloid, neuritic dystrophy, synaptic density, and oxidative and nitrosative damage to brain proteins. This strategy will achieve the specific aims of 1) determining if TM prevents amyloid pathology 2) determining if TM prevents amyloid-associated neuronal damage 3) determining if TM attenuates established beta amyloid pathology and 4) determining if TM attenuates established amyloid-associated neuronal damage. These are the critical pieces of information for determining if TM should be evaluated in clinical trials for either the prevention or the treatment of Alzheimer's disease.