Changes in the brain transcriptome after DNA Aß42 trimer immunization in a 3xTg-AD mouse model.

Alzheimer's disease (AD) has been associated with accumulation of amyloid beta (Aß) peptides in brain, and immunotherapy targeting Aß provides potential for AD prevention. We have used a DNA Aß42 trimer construct for immunization of 3xTg-AD mice and found previously significant reduction of amyloid and tau pathology due to the immunotherapy. We show here that DNA Aß42 immunized 3xTg-AD mice showed better performance in nest building activities and had a higher 24 months survival rate compared to the non-treated AD controls. The analysis of differently expressed genes in brains from 24 months old mice showed significant increases transcript levels between non-immunized AD mice and wild-type controls for genes involved in microglia and astrocyte function, cytokine and inflammatory signaling, apoptosis, the innate and adaptive immune response and are consistent with an inflammatory phenotype in AD. Most of these upregulated genes were downregulated in the DNA Aß42 immunized 3xTg-AD mice due to the vaccine. Transcript numbers for the immediate early genes, Arc, Bdnf, Homer1, Egr1 and cfos, involved in neuronal and neurotransmission pathways which were much lower in the non-immunized 3xTg-AD mice, were restored to wild-type mouse brain levels in DNA Aß42 immunized 3xTg-AD mice indicating positive effects of DNA Aß42 immunotherapy on synapse stability and plasticity. The immune response after immunization is complex, but the multitude of changes after DNA Aß42 immunization shows that this response moves beyond the amyloid hypothesis and into direction of disease prevention.