RESUMEN
The aggregation of amyloid ß-peptide (Aß) is thought to play a pivotal role in the disease progression of Alzheimer's disease (AD). Amyloid ß directed immunotherapy has been considered an alternative AD treatment. In this study, we constructed a DNA vaccine, p(Aß3-10)10-mIL-4, encoding ten tandem repeats of Aß3-10 fused with mouse IL-4. Eight-month-old APP/PS1 transgenic mice were injected intramuscularly with p(Aß3-10)10-mIL-4 followed by in vivo electroporation. Immunization with the vaccine induced high-titer anti-Aß antibodies and attenuated the behavior impairment. Immunoglobulin isotyping revealed a predominantly IgG1 response and ex vivo cultured splenocytes exhibited a low IFN-γ and high IL-4 response, indicating a Th2 anti-inflammatory response. Immunohistochemical analysis revealed that p(Aß3-10)10-mIL-4 immunization decreased Aß deposition, and the microglial attraction significantly decreased accompanied by the clearance of Aß. There was no microhemorrhage in the brain of the immunized mice. These results suggest that the immunization potentially reduced the inflammation in brain of transgenic mice and therefore improved their cognitive ability. This novel DNA vaccine p(Aß3-10)10-mIL-4 may be an effective immunization method as therapy for AD.
Asunto(s)
Precursor de Proteína beta-Amiloide , Corteza Cerebral/efectos de los fármacos , Trastornos del Conocimiento/tratamiento farmacológico , Electroquimioterapia/métodos , Presenilina-1 , Vacunación/métodos , Vacunas de ADN/administración & dosificación , Precursor de Proteína beta-Amiloide/genética , Animales , Corteza Cerebral/patología , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Femenino , Células HEK293 , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Ratones , Ratones Transgénicos , Presenilina-1/genéticaRESUMEN
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 Aß to promote humoral immunity. In this study, we developed a novel vaccine [p(Aß3-10)10-MT] that expresses ten repeats of Aß3-10 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(Aß3-10)10-MT vaccine induced high titers of anti-Aß antibodies, which in turn reduced Aß 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(Aß3-10)10-MT may potentially be an effective vaccine to reduce accumulated Aß and attenuate cognitive deficits.
