This a resubmission of a proposal that previously received an acceptable score. It is a collaborative project between Dr. Cotman's neuroanatomy lab at UC Irvine, and Dr. Milgrim's neurobehavioral lab at the the University of Toronto. The current proposal additionally includes a large colony of dogs at the Inhilation Toxicology Research Institute in New Mexico, directed by Dr. Muggenburg.The investigators propose that the aged canine is an appropriate model for studying the earliest, and perhaps most critical stages of Alzheimer's Disease. There is extensive deposition of beta amyloid in the aged canine brain, but the canine does not appear to progress to the later stages of senile plaque formation, nor are neurofibrillary tangles present. To date there has been no examination of how neuropatholgical changes in the aged canine relate to changes in cognitive ability. In this proposal, dogs of varying ages will be tested on a battery of neuropsychological tests to determine which are most sensitive to early changes in learning and memory, and to determine whether procedural tasks, which are relatively spared in aged humans, are similarly spared in aged canines. The current proposal has added olfactory tasks to the battery, as well as assessment of sensory performance. Tasks will be refined at the University of Toronto, and dogs will be tested at either the University of Toronto or the ITRI. Following sacrifice, Dr. Cotman's lab will: 1) quantify the level of b-amyloid accumulation, including assessment of vascular changes (amyloid angiopathy), 2) address synapse number using synaptophysin immunoreactivity, and 3) examine cytoskeletal changes using antibodies to phosphorylated (SMI-31, SMI-34, SMI-310) and non-phosphorylated (SMI-32, SMI- 311) neurofilament epitopes, and different phosphorylation sites on the microtubual associated proteins tau (tau-1, PHF-1, AT8), MAP2 and MAP5. Tissue will also be examined for other neuropathologic changes such as neuritic dystrophy. The hippocampus, entorhinal cortex, superior frontal cortex and cerebellum will be the focus of these examinations; the first three due to their involvement in the cognitive tasks examined and their vulnerability in Alzheimer's Disease. The cerebellum will serve as a control, as this area is relatively unaffected by Alzheimer's, and is less directly linked with the cognitive tasks under examination. Behavioral changes will be correlated with neuropathological findings in hopes of better understanding which component of pathology occurs first and/or contributes the most to age-related cognitive decline.
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