Alzheimer’s disease (AD) is the most common form of dementia and currently has no disease-modifying treatments. It has become increasingly evident that various non-neuronal cell types in the brain, such as glia and endothelial cells, play important roles in promoting and preventing neurodegeneration. In mouse models of AD, physical isolation of microglia has been leveraged to define the “degeneration-associated microglia” (DAM) signature and demonstrate its dependence on the immunoreceptor Trem2. However, cell-intrinsic responses of other cell types are less well understood because of technical limitations in isolating other brain cells. In this study, we first utilized single-nucleus RNA sequencing (snRNA Seq) to characterize transcriptional changes across brain cell types in 5XFAD and non-5XFAD mice with or without Trem2 expression. We identified a distinct oligodendrocyte activation signature. Immunofluorescence microscopy and proteomics confirmed upregulation of these genes in amyloid plaque-adjacent oligodendrocytes. Next, we performed behavioral analysis of 5XFAD and Trem2-deficient 5XFAD mice, showing for the first time that Trem2 deficiency exacerbates memory and anxiety phenotypes in 5XFAD mice. Finally, we analyzed human AD samples using NanoString solutions and snRNA Seq. Pathway analysis with NanoString solutions identified overarching changes that were assigned to cell-specific contributions using snRNA Seq findings. This approach confirmed holistic findings such as oligodendrocyte and microglia changes but not upregulation of the exact activation signature genes found in mice.
FOR RESEARCH USE ONLY. Not for use in diagnostic procedures.