ABSTRACT In Alzheimers disease (AD) one finds increased presence of monocytes/macrophages and activated microglial cells in the brain. Immunohistochemical studies show increased expression of CCR5 on reactive microglia associated with amyloid deposits in AD, suggesting that CCR5 may play a role in the regulation of the immune response in AD. Here we used peripheral blood monocytes and human monocytic THP-1 cell line as a model of microglia to delineate the cellular signaling mechanism of A-induced CCR5 expression and the latters role in the chemotaxis of monocytes. We observed that Apeptides at pathophysiological concentrations (125 nM) increased CCR5 mRNA and cell surface protein expression. The cellular signaling involved activation of c-Raf, ERK-1/ERK-2 and c-Jun N-terminal kinase. Analysis of some transcription factors associated with CCR5 promoter revealed that Aincreased DNA binding activity of Egr-1 and AP-1. Additionally, we show that CCR5 promoter contains an Egr-1 like consensus sequence GCGGGGGTG as demonstrated by (i) electrophoretic mobility shift assay, (ii) transfection studies with truncated CCR5 gene promoter construct and (iii) chromatin immunoprecipitation analysis. Moreover, transfection of Egr-1 siRNA, but not of scrambled Egr-1 siRNA, in THP-1 cells resulted in >75% reduction in both A-mediated CCR5 expression and concomitant chemotaxis to its ligands. We suggest that inhibition of Egr-1 by either Egr-1 siRNA or pharmacological agents may reduce activation of monocytes/microglia and possibly ameliorate the inflammation and progression of AD.