Neuroinflammation, which is evident as microglial activation in both the normally aged brain and in the Alzheimer's disease (AD) brain, is thought to be a contributing factor in neurodegeneration. The cause(s) of glial neuroinflammation are unknown, since it occurs in the absence of obvious neuronal injury. In this proposal, we will investigate the novel hypothesis that microglial senescence accounts for the observed glial neuroinflammation in the aging brain. We postulate that microglial cells are subject to an age-related decline in cellular structure and function that results from multiple, interconnected etiologies, including structural deterioration of cell cytoplasm, increased apoptosis, replicative senescence, and telomere shortening and/or concomitantly altered telomerase activity. Thus, """"""""diseased"""""""" microglia could be responsible, in part, for age-related neurodegenerative changes due to a progressive loss of glial trophic support for neurons over time.
The specific aims are designed to investigate multiple aspects of the presumed microglial senescence and dysfunction using a variety of approaches that include human post-mortem tissue, experimental studies in rats, as welt as studies in cell culture. They are as follows:
Specific Aim 1 : To analyze morphological abnormalities associated with microglial cells in the human brain using post-mortem tissue from both AD and non-demented, age-matched individuals.
Specific Aim 2 : To determine whether microglia, the only mature cell type in the CNS with significant mitotic potential, are subject to replicative senescence. These studies are to be performed in young and old rats using the facial nerve system as a reproducible model for stimulating microglial mitosis.
Specific Aim 3 : To determine whether microglial cells undergo telomere shortening and exhibit decreased telomerase activity with increasing time in vitro.
Specific Aim 4 : To determine whether microglial cells undergo telomere shortening and exhibit altered gene expression with aging in vivo. It is anticipated that results from the proposed studies will provide new insights into degenerative microglial cell changes that occur with aging. Preliminary studies suggest that microglial degeneration is much more pronounced in AD compared to non-demented individuals, and thus microglial dysfunction could be an important factor in AD pathogenesis.
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