Enhancing Th2 immune responses against amyloid protein by a DNA prime-adenovirus boost regimen for Alzheimer's disease

Abstract Accumulation of aggregated amyloid β-protein (Aβ) in the brain is thought to be the initiating event leading to neurodegenetation and dementia in Alzheimer's disease (AD). Therefore, therapeutic strategies that clear accumulated Aβ and/or prevent Aβ production and its aggregation are predicted to be effective against AD. Immunization of AD mouse models with synthetic Aβ prevented or reduced Aβ load in the brain and ameliorated their memory and learning deficits. The clinical trials of Aβ immunization elicited immune responses in only 20% of AD patients and caused T-lymphocyte meningoencephalitis in 6% of AD patients. In attempting to develop safer vaccines, we previously demonstrated that an adenovirus vector, AdPEDI-(Aβ1–6)11 , which encodes 11 tandem repeats of Aβ1-6 can induce anti-inflammatory Th2 immune responses in mice. Here, we investigated whether a DNA prime-adenovirus boost regimen could elicit a more robust Th2 response using AdPEDI-(Aβ1–6)11 and a DNA plasmid encoding the same antigen. All mice ( n = 7) subjected to the DNA prime-adenovirus boost regimen were positive for anti-Aβ antibody, while, out of 7 mice immunized with only AdPEDI-(Aβ1–6)11 , four mice developed anti-Aβ antibody. Anti-Aβ titers were indiscernible in mice ( n = 7) vaccinated with only DNA plasmid. The mean anti-Aβ titer induced by the DNA prime-adenovirus boost regimen was approximately 7-fold greater than that by AdPEDI-(Aβ1–6)11 alone. Furthermore, anti-Aβ antibodies induced by the DNA prime-adenovirus boost regimen were predominantly of the IgG1 isotype. These results indicate that the DNA prime-adenovirus boost regimen can enhance Th2-biased responses with AdPEDI-(Aβ1–6)11 in mice and suggest that heterologous prime-boost strategies may make AD immunotherapy more effective in reducing accumulated Aβ.