DNA Aβ42 Immunotherapy Induces Epigenetic Changes of the Gene Expression Profile in Brain in the 3XTG‐AD Mouse Model

AbstractBackgroundAlzheimer's disease (AD) has been associated with deposition of amyloid beta (Aβ) peptides in brain, and immunotherapy targeting Aβ provides potential for AD prevention. We have used a DNA Aβ42 trimer construct for immunization of 3xTg‐AD mice and found significant reduction of amyloid and tau pathology. Our working hypothesis is that DNA Aβ42 immunotherapy affects the gene expression profiles in brains of the treated mice, and is thus changing the microenvironment for possible AD prevention.MethodsMice were immunized with DNA Aβ42 trimer in 6‐week intervals during the experimental time line (24 months). Amyloid and tau pathology was evaluated in brains by immunohistochemistry. FFPE sections from DNA Aβ42 immunized 3xTg‐AD mice, non‐treated 3xTg‐AD controls and age and gender matched wild‐type controls (n=4/group) were used for RNA isolation and gene expression analysis using a Neuroinflammation gene panel (Nanostring nCounter).ResultsThe analysis of differently expressed genes in brains from 24 months old mice showed significant changes in transcript levels between non‐immunized AD mice and wild‐type controls for genes involved in microglia (Trem2, Ccl3, Ccl4, Csf1, CD68, CD84, Apoe, Itax1, Irf8, Ctse, Ctss) and astrocyte function (Lnc2, CD14, CD109, CD72, Vim, S100a10), cytokine and inflammatory signaling (Mpec1, Btk, Ssp1, Il1r1, Il6a, Inpp5d, Ch25h, Lilrb4a, Syk, Tgb1), matrix remodeling (Ptprc, Ssp1, Mmp2, Tgfb1), apoptosis (Bcl2a1, Bax, Casp4, Casp8, Fas), the innate (C1qa, C1qb, C3ar1, C4a, Btk, Tyrobp, Ly6a, Syk) and adaptive immune response (CD74, Btk, Ctse, Ctss, Fcer1g, Fcr2b, Inpp5d, Lilrb4a), consistent with an inflammatory phenotype in AD. These genes were also changed in the DNA Aβ42 immunized 3xTg‐AD mice compared to the non‐immunized AD mice nudging into direction of the wild‐type controls indicative of downregulation of inflammation due to immunotherapy, respectively. Significant changes were found for the immediate early genes, Bdnf, Arc, Homer1, Egr1 and c‐fos, involved in neuronal and neurotransmission pathways which were higher expressed in DNA Aβ42 immunized 3xTg‐AD mice and wild‐type controls compared to non‐immunized 3xTg‐AD mice indicating effects of DNA Aβ42 immunotherapy on synapse plasticity and memory formation.ConclusionThe multitude of changes after DNA Aβ42 immunization shows that this intervention has high potential for disease prevention.