MATERNAL DNA-IMMUNIZATION STRATEGY TARGETING AMYLOID-β RELATED NEUROPATHOLOGY AND DEMENTIA IN DOWN-SYNDROME

Down Syndrome (DS) is characterized by overexpression of the APP and DYRK1A genes, located on the triplicated chromosome 21, leading to cognitive decline mediated by Amyloid-β (Aβ) overproduction and tau hyper-phosphorylation. Since DS can be detected in utero, maternal vaccination against Aβ at early developmental stages, could delay dementia onset in DS. To test this, WT female mice were DNA-vaccinated using electroporation with a sham vaccine or the Aβ_1-11 antigen. Following this, female mice were crossbred with male 5xFAD mice which model AD. The transgenic pups were then actively vaccinated at the age of 1 month with either the Aβ_1-11 or sham vaccine. At 5 months, the transgenic offspring were tested for cognitive capacity and AD-related neuropathology. Maternal vaccination provided passive immunization against Aβ prenatally at E17 and postnatally until p28. 5xFAD mice that were exposed to passive immunization alone or in combination with active immunization at 1 month exhibited normalized exploratory behavior, along with alleviation of short-term memory deficits compared with non-vaccinated controls. Further, a combined maternal and active vaccinations induced equivalent reduction in cortical Aβ levels as that of passive immunization alone, suggesting that early maternal immunization is sufficient to elicit Aβ clearance. This process is mediated by elevation of cerebral FcγRs and FcRn levels at 5m, results in enhanced phagocytosis by microglial cells. Thus, maternal Anti-Aβ immunization confers long-term beneficial effects in the offspring, possibly by facilitation of FcR-mediated phagocytosis, resulting in Aβ-clearance and amelioration of cognitive deficits.