Short amyloid-β (Aβ) immunogens reduce cerebral Aβ load and learning deficits in an Alzheimer's disease mouse model in the absence of an Aβ-specific cellular immune response

Amyloid-β(Aβ) immunotherapy lowers cerebral Aβand improves cognition in mouse models of Alzheimer's disease (AD). A clinical trial using active immunization with Aβ1-42 was suspended after ∼6% of patients developed meningoencephalitis, possibly because of a T-cell reaction against Aβ. Nevertheless, beneficial effects were reported in antibody responders. Consequently, alternatives are required for a safer vaccine. The Aβ1-15 sequence contains the antibody epitope(s) but lacks the T-cell reactive sites of full-length Aβ1-42. Therefore, we tested four alternative peptide immunogens encompassing either a tandem repeat of two lysine-linked Aβ1-15 sequences (2XAβ1-15) or the Aβ1-15 sequence synthesized to a cross-species active T1 T-helper-cell epitope (T1-Aβ1-15) and each with the addition of a three-amino-acid RGD (Arg-Gly-Asp) motif (R-2XAβ1-15; T1-R-Aβ1-15). High anti-Aβ antibody titers were observed in wild-type mice after intranasal immunization with R-2XAβ1-15 or 2XAβ1-15 plus mutant Escherichia coli heat-labile enterotoxin LT(R192G) adjuvant. Moderate antibody levels were induced after immunization with T1-R-Aβ1-15 or T1-Aβ1-15 plus LT(R192G). Restimulation of splenocytes with the corresponding immunogens resulted in moderate proliferative responses, whereas proliferation was absent after restimulation with full-length Aβ or Aβ1-15. Immunization of human amyloid precursor protein, familial AD (hAPP_FAD) mice with R-2XAβ1-15 or 2XAβ1-15 resulted in high anti-Aβ titers of noninflammatory T-helper 2 isotypes (IgG1 and IgG2b), a lack of splenocyte proliferation against full-length Aβ, significantly reduced Aβ plaque load, and lower cerebral Aβ levels. In addition, 2XAβ1-15-immunized hAPP_FAD animals showed improved acquisition of memory compared with vehicle controls in a reference-memory Morris water-maze behavior test that approximately correlated with anti-Aβ titers. Thus, our novel immunogens show promise for future AD vaccines.