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Copper Complexing with Tetrathiomolybdate in a Murine Model of Alzheimers Disease

阿尔茨海默病小鼠模型中铜与四硫代钼酸盐的络合

基本信息

批准号：
7282681
负责人：
JOSEPH F QUINN
金额：
$ 13.48万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7282681
关键词：
Age Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Animals Antibiotics Appearance Attenuated Behavioral Binding Biochemical Brain Cerebrum Ceruloplasmin Chelating Agents Cholesterol Chronic Clinical Clinical Trials Clioquinol Complex Condition Copper Dose Generations Goals Hepatolenticular Degeneration Hydrogen Peroxide In Vitro Investigational Drugs Memory Memory impairment Metals Modeling Molecular Conformation Molybdenum Monitor Motor Mus Nerve Degeneration Nervous System Physiology Neurologic Neurons Neuroprotective Agents Oral Outcome Measure Pathology Physiological Plasma Polymers Population Prevention Process Property Proteins Randomized Role Safety Synapses Testing Tg2576 Tissue Harvesting Toxic effect Transgenic Organisms Weight Wild Type Mouse Zinc amyloid pathology base beta amyloid pathology brain tissue clinical application cohort cytochrome c oxidase density human subject indexing interest morris water maze mouse model neurotoxic prevent research study tetrathiomolybdate treatment duration

项目摘要

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.

描述（由申请人提供）：本申请的目的是确定四硫钼酸盐的铜络合特性是否在阿尔茨海默病小鼠模型中具有足够的抗淀粉样蛋白或神经保护作用，以证明该研究药物的临床试验是合理的。