Gene vaccination to bias the immune response to amyloid-β peptide as therapy for Alzheimer disease

Background: The amyloid-β (Aβ) peptide has a central role in the neurodegeneration of Alzheimer disease (AD). Immunization of AD transgenic mice with Aβ_1-42 (Aβ₄₂) peptide reduces both the spatial memory impairments and AD-like neuropathologic changes in these mice. Therapeutic immunization with Aβ in patients with AD was shown to be effective in reducing Aβ deposition, but studies were discontinued owing to the development of an autoimmune, cell-mediated meningoencephalitis. We hypothesized that gene vaccination could be used to generate an immune response to Aβ₄₂ that produced antibody response but avoided an adverse cell-mediated immune effect. Objective: To develop an effective genetic immunization approach for treatment and prevention of AD without causing an autoimmune, cell-mediated meningoencephalitis. Methods: Mice were vaccinated with a plasmid that encodes Aβ₄₂, administered by gene gun. The immune response of the mice to Aβ₄₂ was monitored by measurement of (1) antibody levels by enzyme-linked immunosorbent assay (ELISA) and Western blot and (2) Aβ₄₂-specific T-cell response as measured by interferon-γ enzyme-linked immunospot (ELISPOT) assay. Results: Gene-gun delivery of the mouse Aβ₄₂ dimer gene induced significant humoral immune responses in BALB/c wild-type mice after 3 vaccinations in 10-day intervals. All 3 mice in the treated group showed significant humoral immune responses. The ELISPOT assay for interferon-γ release with mouse Aβ₄₂ peptide and Aβ_9-18 showed no evident cytotoxic T-lymphocyte response. We further tested the responses of wild-type BALB/c mice to the monomer Aβ₄₂ gene vaccine. Western blot evaluation showed both human and mouse Aβ monomer gene vaccine elicited detectable humoral immune responses. We also introduced the human Aβ₄₂ monomer gene vaccine into AD double transgenic mice APPswe/PSEN1(A246E). Mice were vaccinated with plasmids that encode Aβ_1-42 and Aβ_1-16 or with plasmid without the Aβ gene. Treated mice showed significant humoral immune responses as demonstrated by ELISA and by Western blot. These mice also showed no significant cellular immune response as tested by ELISPOT. One of the treated mice was killed at 7 months of age for histological observations, and scattered amyloid plaques were noted in all layers of the cerebral cortex and in the hippocampus in both Aβ₄₂- and control-vaccinated mice. No definite difference was discerned between the experimental and control animals. Conclusions: Gene-gun-administered genetic immunization with the Aβ₄₂ gene in wild-type BALB/c and AD transgenic mice can effectively elicit humoral immune responses without a significant T-cell-mediated immune response to the Aβ peptide. This immunotherapeutic approach could provide an alternative active immunization method for therapy and prevention of AD.