Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer's disease

Resolving glial contributions to Alzheimer???s disease (AD) is necessary because changes in neuronal function, such as reduced synaptic density, altered electrophysiological properties, and degeneration, are not entirely cell autonomous. To improve understanding of transcriptomic heterogeneity in glia during AD, we used single-nuclei RNA sequencing (snRNA-seq) to characterize astrocytes and oligodendrocytes from apolipoprotein (APOE) ??2/3 human AD and age-and genotype-matched non-symptomatic (NS) brains. We enriched astrocytes before sequencing and characterized pathology from the same location as the sequenced material. We characterized baseline heterogeneity in both astrocytes and oligodendrocytes and identified global and subtype-specific transcriptomic changes between AD and NS astrocytes and oligodendrocytes. We also took advantage of recent human and mouse spatial transcriptomics resources to localize heterogeneous astrocyte subtypes to specific regions in the healthy and inflamed brain. Finally, we integrated our data with published AD snRNA-seq datasets, highlighting the power of combining datasets to resolve previously unidentifiable astrocyte subpopulations.

Automated summary

This study used single-nuclei RNA sequencing to investigate the transcriptomic heterogeneity of astrocytes and oligodendrocytes in Alzheimer's disease (AD) patients. The findings revealed global and subtype-specific transcriptomic changes in these glial cells between AD and non-symptomatic brains, as well as the localization of heterogeneous astrocyte subtypes in specific brain regions using spatial transcriptomics resources.