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Cognitive Decline &Protein Expression Profiles in Aging

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This proposal is designed to assess age-related changes in protein expression profiles in discrete areas of the hippocampus of behaviorally defined animals. Even in the absence of overt pathological processes, cognitive function decreases with age. To isolate the mechanisms that contribute to the decline in learning and memory, studies of the effects of interventions that delay, or reverse the age-related decline in function are required. One of the factors that contributes to brain aging is IGF-1. IGF-1 decreases in the brain with age;systemic administration of GHRH or growth homrone or central administration of IGF-1 improves synaptic profiles and glucose metabolism, reverses the age-related decline in NMDAR2a and 2b and improves cognitive ability. Although much information related to brain aging is known, the mechanisms responsible for brain aging and potential therapeutic targets to delay or reverse brain aging remain poorly understood. Since brain aging is undoubtedly based in alterations in protein expression, advances in our understanding of brain aging require 1) a thorough analysis of protein expression patterns in specific brain regions that have a relevant behavioral basis and 2) analysis of changes in protein expression patterns after interventions known to impact cognitive ability in older animals. Our overall hypothesis is that the age-related decline in frontal lobe-dependent and hippocampally-dependent performance on tasks of learning and memory result from altered protein expression profiles within the prefrontal cortex and CA1, CA2/3 and dentate regions of the hippocampus, respectively. Specific aims are to: 1) Assess age-related changes in protein expression profiles within the relevant regions of the hippocampus in behaviorally defined animals;2) Determine the effect of GH/IGF-1 replacement on protein expression profiles within these regions;and 3) Assess the effects of a novel model of adult-onset GH/IGF-1 deficiency on cognitive function and protein expression profiles within CA1, CA2/3 and dentate regions of the hippocampus. Studies will use 2-Dimensional Difference in Gel Electrophoresis (2-DIGE) for proteomic scale protein quantification and MALDI-ToF/ToF mass spectrometry for protein identification. The results will provide the first comprehensive investigation of age-related changes in the proteome in discrete brain regions that contributes to cognitive deficits with age.

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