Background: Immunotherapy for Alzheimer's disease (AD) is emerging as a potential treatment. However, a clinical trial (AN1792) was halted after adverse effects occurred in a small subset of subjects, which may have been caused by a T cell-mediated immunological response. In general, aging limits the humoral immune response, therefore, immunogens and vaccination regimes are required that induce a strong antibody response with less potential for an adverse immune response.
Method: In the current study, we immunized both wildtype and J20 APP-tg mice with a priming injection of Abeta1-40/42, followed by multiple intranasal boosts with the novel immunogen dAbeta1-15 (16 copies of Abeta1-15 on a lysine tree), Abeta1-15 peptide or Abeta1-40/42 full length peptide.
Results: J20 APP-tg mice primed with Abeta1-40/42 subcutaneously and subsequently boosted intranasally with Abeta1-15 peptide did not generate a cellular or humoral immune response. In contrast, J20 APP-tg mice boosted intranasally with dAbeta1-15 or full length Abeta1-40/42 produced high levels of anti-Abeta antibodies. Splenocyte proliferation was minimal in mice immunized with dAbeta1-15. Wildtype littermates of the J20 APP-tg mice produced higher amounts of anti-Abeta antibodies compared to APP-tg mice but also had low T cell proliferation. The anti-Abeta antibodies were mainly composed of IgG2b and directed to an epitope within the Abeta1-7 region, regardless of the immunogen. Examination of the brain showed a significant reduction in Abeta plaque burden in the J20 APP-tg mice producing antibodies compared to controls. Biochemically, Abeta40 or Abeta42 were also reduced in brain homogenates and elevated in plasma but the changes did not reach significance.
Conclusion: Our results demonstrate that priming with full length Abeta40/42 followed by boosting with dAbeta1-15 but not Abeta1-15 peptide led to a robust humoral immune response with a minimal T cell response in J20 APP-tg mice. In addition, Abeta plaque burden was reduced in mice producing anti-Abeta antibodies. Interestingly, wildtype mice produced higher levels of anti-Abeta antibodies, indicating that immune tolerance may be present in J20 APP-tg mice. Together, these data suggest that dAbeta1-15 but not Abeta1-15 peptide may be useful as a boosting immunogen in an AD vaccination regime.