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. ? ? ?
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| Quinn, Joseph F; Harris, Christopher J; Cobb, Katherine E et al. (2010) A copper-lowering strategy attenuates amyloid pathology in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis 21:903-14 |
| Wadsworth, Teri L; Bishop, James A; Pappu, Anuradha S et al. (2008) Evaluation of coenzyme Q as an antioxidant strategy for Alzheimer's disease. J Alzheimers Dis 14:225-34 |
