Active immunization with amyloid-beta 1–42 induces severe memory impairment in healthy mice

Active immunization with Amyloid-beta 1–42 (Abeta) was shown to prevent amyloid plaque deposition in different mouse models of Alzheimer's disease (AD). These effects are undoubted, whereas evidence on the improvement of memory function is still inconsistent. Here, we identify the cognitive and immunological phenotype of healthy C57BL/6 mice challenged with active Abeta immunization. Immunization significantly altered the behavioural phenotype of mice compared to control mice receiving the immune stimulant only or Myelin oligodendrocyte glycoprotein induced EAE mice. Abeta immunized mice revealed decreased locomotor activity, reduced habituational learning and highly deficient spatial-learning abilities in an object recognition task. Quantitative rtPCR data demonstrated the upregulation of a number of macrophage and T cell related genes in the CNS of Abeta mice, in particular C3, CD3, CD14, Cxcl10, IL-1b, IFN-g and S100A8. Furthermore, reactive gliosis was detected in Abeta mice in the chronic phase of disease as shown by GFAP immunohistochemistry and by quantitative rtPCR for GFAP. In peritoneal macrophages from immunized mice, CD14, CSF 3, IL-1b, IL-6, MMP9, Nos2, S100A8 and TNF-a gene transcripts were highly upregulated. In summary, immunization with Abeta induced an inflammatory cascade significantly impairing cognitive functioning. This process is mainly mediated by the recruitment of macrophages locally producing proinflammatory cytokines and evoking CNS tissue damage which is marked by reactive gliosis. These results illustrate the potential danger of active immunization with neuronal antigens and demonstrate the complexity of immune responses to Abeta in the pathogenesis of AD. Abeta immunization in plaque pathology free animals even provides a suitable model for autoimmune mediated cognitive impairment.