Human G protein-coupled formyl peptide receptor like 1 (FPRL1) and its mouse homologue murine formyl peptide receptor 2 (mFPR2) mediate the chemotactic activity of amyloid beta 1-42 (Abeta42), a key pathogenic peptide in Alzheimer's disease (AD). Since mFPR2 is up-regulated in mouse microglia by lipopolysaccharide (LPS), a Toll-like receptor 4 ligand, we investigated the capacity of CpG-containing oligodeoxynucleotide (ODN), a Toll-like receptor (TLR) 9 ligand, to regulate the expression of mFPR2 in mouse microglia. CpG ODN markedly enhanced the expression and function of mFPR2 in microglial cells, which exhibited increased chemotactic responses to mFPR2 agonists, including Abeta42. The effect of CpG ODN is dependent on activation of p38 MAPK. Further studies showed that CpG ODN-treated microglia increased their capacity to endocytose Abeta42 through mFPR2, as this process was abrogated by pertussis toxin, a Gi protein inhibitor, and W peptide, another potent mFPR2 agonist. Our results suggest that TLR9 may play an important role in promoting microglial recognition of Abeta42, thus affecting the pathogenic process of AD.