Abstract
CCAAT-enhancer binding proteins are transcription factors that help to regulate a wide range of inflammatory mediators, as well as several key elements of energy metabolism. Because C/EBPs are expressed by rodent astrocytes and microglia, and because they are induced by pro-inflammatory cytokines that are chronically upregulated in the Alzheimer’s disease (AD) cortex, we have investigated whether C/EBPs are expressed and upregulated in the AD cortex. Here, we demonstrate for the first time that C/EBPβ can be detected by Western blots in AD and nondemented elderly (ND) cortex, and that it is significantly increased in AD cortical samples. In situ, C/EBPβ localizes immunohistochemically to microglia. In microglia cultured from rapid autopsies of elderly patient’s brains and in the BV-2 murine microglia cell line, we have shown that C/EBPβ can be upregulated by C/EBP-inducing cytokines or lipopolysaccharide and exhibits nuclear translocation possibly indicating functional activity. Given the known co-regulatory role of C/EBPs in pivotal inflammatory mechanisms, many of which are present in AD, we propose that upregulation of C/EBPs in the AD brain could be an important orchestrator of pathogenic changes.
Highlights
Chronic, micro-localized inflammation, consisting primarily of innate and acute phase mechanisms, is widely regarded as a potentially important pathogenic element in Alzheimer’s disease (AD)
We reported for the first time that C/EBPd is present in the human brain and is upregulated in the AD cortex, with predominant localization to astrocytes [14]
We have previously reported that C/EBPd is present in the human brain, upregulated in AD brain astrocytes, and functionally responsive to cytokine stimulation in human post-mortem astrocyte cell cultures [14]
Summary
Micro-localized inflammation, consisting primarily of innate and acute phase mechanisms, is widely regarded as a potentially important pathogenic element in Alzheimer’s disease (AD). Transcription factors represent a primary point for regulation of gene and subsequent protein expression, and they typically act on sets of genes within multiple pathways. As such, they are in a position to broadly organize cellular responses, including pathogenic responses. C/EBP family members C/ EBPb and C/EBPd can be important co-regulators with nuclear factor-kB (NF-kB) in a host of inflammatory responses [8,9,10,11,12], this role appears to have been largely overlooked in AD studies of NF-kB-related mechanisms. Because the protein products of many of the inflammatory genes of which the C/ EBPs have been shown to regulate in the periphery [5,6,13] are known to be altered in AD [1], our goal is determining which
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