Boosting with intranasal dendrimeric Abeta1-15 but not Abeta1-15 peptide leads to an effective immune response following a single injection of Abeta1-40/42 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.


METHODS
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.


CONCLUSIONS
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.
Seabrook
Timothy J
TJ
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. tseabrook@rics.bwh.harvard.edu
Jiang
Liying
L
Thomas
Katelyn
K
Lemere
Cynthia A
CA