Differences in the brain transcriptome of glial genes due to aging and active DNA Aβ42 and passive MOAB anti‐Aβ immunotherapy in the 3xTg‐AD mouse strain

Abstract

Microglia and astrocytes are key players in brain health and disease. Investigating changes in glia gene expression pattern provides further insight into how these cells respond to a progressing AD pathology as well as to changes resulting from removal of pathology components due to anti-Aβ immunotherapy.Mice were immunized with DNA Aβ42 trimer or received passive immunotherapy with the mouse moab 6E10 during the experimental timeline (20 months). Amyloid and tau pathology was evaluated in brains by immunohistochemistry. FFPE sections from the different mouse groups (five groups, n=4/group) were used for transcriptome analyses. Total RNA was isolated from 40 μm FFPE sections and transcript levels for glial genes were determined using the Mouse nCounter Glial Profiling Panel (Nanostring) of 753 genes covering the core pathways, processes, and phenotypic markers of glial cells.We present here a longitudinal analysis for brains from 2, 10, and 20 months old 3xTg-AD mice, and a cross-sectional study for comparison of changes in the brain transcriptome in a group of 20 months old wild-type controls and three groups of 20 months old 3xTg-AD mice which were either treated with active DNA Aβ42 immunization or passive immunotherapy with the anti-Aβ antibody 6E10, or left untreated as controls. In the longitudinal analysis, for 2-, 10-, and 20-months old mice, 13 genes were identified, Tyrobp, Clec7a, Gfap, Gpnmb, Chil1, C1qa, C1qb, C1qc, Cd14, Ctsd, C3, C3ar1, and Trem2, for which high expression could be attributed to AD pathology progression. In a cross-sectional comparison of the two anti-Aβ immunotherapy approaches DNA Aβ42 immunized mice showed more benefits with downregulation of inflammatory glial genes in comparison to mice which had received passive moab immunizations. Transcript of eleven genes, Trem2, Chil1, Gpnmb, Fcrls, Clec7a, C1qa, Tyrobp, Cd68, Apoe, Ctsd, Cst7, were lower in the DNA Aβ42 immunized mice than in the passive moab immunized mice.These data shown here for the first time indicate that active DNA Aβ42 immunotherapy has higher impact on a downregulation of glia activation than passive immunotherapy. Results from this analysis are important for future clinical trials using active anti-amyloid immunotherapy.