In Vivo Electroporation of a New Gene Vaccine Encoding Ten Repeats of Aβ3-10 Prevents Brain Aβ Deposition and Delays Cognitive Impairment in Young Tg-APPswe/PSEN1dE9 Mice

摘要

Active immunization holds great promise for the treatment of Alzheimer’s disease but the infiltration of T-lymphocytes and associated meningoencephalitis observed in clinical trials needs to be overcome. To avoid this toxicity, previous studies have used synthetic truncated derivatives of Aβ to promote humoral immunity. In this study, we developed a novel vaccine [p(Aβ3-10)10-MT] that expresses ten repeats of Aβ3-10 with melatonin (MT) as an adjuvant, and administered it intramuscularly in three-month-old Tg-APPswe/PSEN1dE9 (Tg) mice by in vivo electroporation. The p(Aβ3-10)10-MT vaccine induced high titers of anti-Aβ antibodies, which in turn reduced Aβ deposits in the mouse brains and decreased cognitive impairment. Immunoglobulin isotyping revealed a predominantly IgG1 response, indicating a Th2 anti-inflammatory response. Ex vivo cultured splenocytes exhibited a low IFN-γ and high IL-4 response. Immunohistochemical analysis revealed that glial cell activation was also attenuated. These results indicate that p(Aβ3-10)10-MT may potentially be an effective vaccine to reduce accumulated Aβ and attenuate cognitive deficits.