Boosting with intranasal dendrimeric Aβ1–15 but not Aβ1–15 peptide leads to an effective immune response following a single injection of Aβ1–40/42 in APP-tg mice

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 Aβ1-40/42, followed by multiple intranasal boosts with the novel immunogen dAβ1-15 (16 copies of Aβ1-15 on a lysine tree), Aβ1-15 peptide or Aβ1-40/42 full length peptide. RESULTS: J20 APP-tg mice primed with Aβ1-40/42 subcutaneously and subsequently boosted intranasally with Aβ1-15 peptide did not generate a cellular or humoral immune response. In contrast, J20 APP-tg mice boosted intranasally with dAβ1-15 or full length Aβ1-40/42 produced high levels of anti-Aβ antibodies. Splenocyte proliferation was minimal in mice immunized with dAβ1-15. Wildtype littermates of the J20 APP-tg mice produced higher amounts of anti-Aβ antibodies compared to APP-tg mice but also had low T cell proliferation. The anti-Aβ antibodies were mainly composed of IgG2b and directed to an epitope within the Aβ1-7 region, regardless of the immunogen. Examination of the brain showed a significant reduction in Aβ plaque burden in the J20 APP-tg mice producing antibodies compared to controls. Biochemically, Aβ40 or Aβ42 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 Aβ40/42 followed by boosting with dAβ1-15 but not Aβ1-15 peptide led to a robust humoral immune response with a minimal T cell response in J20 APP-tg mice. In addition, Aβ plaque burden was reduced in mice producing anti-Aβ antibodies. Interestingly, wildtype mice produced higher levels of anti-Aβ antibodies, indicating that immune tolerance may be present in J20 APP-tg mice. Together, these data suggest that dAβ1-15 but not Aβ1-15 peptide may be useful as a boosting immunogen in an AD vaccination regime.