The CCAAT-enhancer binding protein (C/EBP) family of transcription factors, particularly C/EBPdelta, is well known to regulate or co-regulate a wide range of inflammatory mediators and mechanisms in the periphery, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). These cytokines, in turn, can induce C/EBPdelta expression and translocation to the nucleus as an active transcription factor. Because IL-1, IL-6, and TNF-alpha are increased in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, we sought to determine if C/EBPdelta might be expressed in AD cortex. Immunohistochemistry of AD tissue sections revealed profuse C/EBPdelta staining of astrocytes, particularly reactive astrocytes surrounding amyloid beta peptide deposits. Substantially less immunoreactivity was observed in comparable sections from nondemented elderly control (ND) patients. These qualitative findings were consistent with quantitative Western blot densitometry results showing significant increases in C/EBPdelta in AD compared to ND cortex samples. Additional in vitro studies were pursued in order to characterize functional activity of C/EBPdelta in human elderly astrocytes. Consistent with a functionally active transcription factor, C/EBPdelta immunoreactivity predominated in the nucleus of cultured AD and ND astrocytes, and exhibited increases and nuclear localization, as determined by Western blots and electrophoretic mobility shifts after exposure to C/EBPdelta-inducing cytokines.