We have previously identified regions of the monkey brain that exhibit morphological signs of damage with age (i.e., subcortical nuclei, white matter ) and other regions that appear relatively well-preserved (i.e., cortical grey matter). The most striking observation is the significant loss of white matter and breakdown of myelin sheaths in the aged monkey brain. Breakdown of myelin may cause aberrant transfer of information leading to cognitive deficits. We hypothesize that some of this damage seen in the cognitively impaired monkeys may be caused by the action of activated astrocytes and microglia and the dysfunction of oligodendrocytes. The goal of this project is to examine morphologically, immunocytochemically and functionally the appearance of the activated glial cells, the induction or inhibition of expression of particular mRNAs, and the production of their related proteins in those regions of the aging brain that may be involved in neurodegeneration. This project will combine morphological and quantitative assessment of all three types of glial cells from young monkeys and compare them with similar assessments in successfully aging and cognitively impaired aging monkeys. We will also perform a functional analysis of the effect of age on these cells using freshly dissected brain slices. Specifically, we will analyze the expression of inflammation-related proteins such as cytokines, complement components and inducible nitric oxide synthase, which can be detrimental to various brain cells, among them the oligodendrocytes. Differential display of cDNAs amplified from specific brain regions will be used as a complementary technique to confirm the differential expression of genes for immune system and inflammatory proteins, and to identify novel genes that are differentially expressed in the three groups of monkeys. In situ hybridization will be used to localize the messages for these genes on a cellular level. As in all projects, the animals used will be categorized according to cognitive state, so that we can determine if changes in the neuroglial cell populations and their functions are related to cognitive decline.
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