Active immunisation with amyloid-β 1–42 severely impairs memory performance in healthy mice through TLR 2/4-dependent activation of the innate immune system

Active immunization with Aβ 1–42 was shown to prevent amyloid plaque deposition in the CNS. However, immunization with Aβ 1–42 may cause meningoencephalitis in human or an experimental autoimmune encephalomyelitis (EAE)-like disease in mice. Recently, we identified cognitive impairment and changes in psychomotor behavior in healthy C57/BL6 mice challenged with active Aβ 1–42 immunization. Immunohistochemistry and gene expression analysis revealed strong recruitment of macrophages and microglia cells in the CNS which was concomitant with severe reactive gliosis in the cerebrum and brainstem. In this study, we primarily focused on the mechanisms triggering CNS inflammation related to Aβ 1–42 immunization. We found a profound induction of TNF and IL-6 protein in naïve macrophages and IFN-γ in dendritic cells stimulated with Aβ 1–42 peptide. Quantitative rtPCR confirmed Aβ 1–42 mediated upregulation of proinflammatory gene transcripts in these cells. Macrophages from mice deficient for the toll-like receptors (TLR) 2/4 did not show any in vitro cytokine induction, suggesting that these receptors are essential for the proinflammatory effects mediated by Aβ 1–42 peptide. In line with this finding, active immunization of TLR 2/4 -/- mice with Aβ 1–42 did not result in the behavioral phenotype observed in wild-type animals. We conclude that psychomotor behavioral changed induced by Aβ immunization are mainly mediated via TLR 2/4 dependent activation of macrophages. These results further demonstrate the proinflammatory properties of Aβ and underline the danger of immunization with autoantigens.