Regulation of Gene Expression in the Aging Brain

Felzien, Lisa

Abstract

The aging process results in decreased brain function caused by neurodegeneration. Strong evidence suggests that the activation of microglial cells increases with age. Since microglial cells function as brain macrophages and secrete cytokines that can be detrimental to neurons, they likely play a role in neurodegeneration. In other systems, the monocyte-chemoattractant protein (MCP)-1 chemokine has been implicated in the recruitment, activation, and proliferation of microglial cells, suggesting that MCP-1 may contribute to the increase in activation of microglial cells in the aged brain. The NF-kappaB and AP-1 families of transcription factors are crucial for MCP-1 expression in several cell types and are altered in the brains of aged animals. NF-kappaB and AP-1 are regulated by the p300/CBP transcriptional co- activators, which enhance transcription by binding to transcription factors and contributing to chromatin remodeling through histone acetylation. The goal of the proposed work is to examine the molecular mechanisms for changes in gene expression that regulate neuro- degeneration associated with normal aging. The hypothesis is that MCP-1 transcription is regulated by NF-kappaB AP-1, and p300/CBP in the aged brain and this results in increased activation of microglial cells. To examine this hypothesis, the following specific aims are proposed: 1) to elucidate the roles of NF-kappaB and AP-1 in regulation of MCP-1 in the brains of aged mice by localizing MCP-1 and AP-1 synthesis and nuclear translocation of NF-kappaB using immunohistochemical and Northern blotting approaches and 2) to examine the interactions between p300/CBP, NF-kappaB, and AP-1 in the brains of aged mice by using immunoprecipitation, Western blotting, and confocal microscopy methods. Elucidation of transcriptional mechanisms for MCP-1 in the aged brain will provide a basis for understanding the mechanisms by which brain function is diminished by the aging process.