GSE160936
Diverse human astrocyte and microglial transcriptional responses to Alzheimer's pathology
To better define roles that microglia and astrocytes play in Alzheimer's disease (AD), we used single-nuclei RNA-sequencing to comprehensively characterize transcriptomes in these glial nuclei isolated post mortem from non-diseased control and neuropathologically-defined AD brains.  Genes associated with AD risk were highly represented, especially in microglia. Transcriptome differences significantly correlated with immunohistochemical phospho-Tau (pTau) density included genetic risk genes for both microglia (APOE, BIN1, MS4A6A, PILRA) and astrocytes (APOE, CLU, MEF2C, IQCK).  Pathways associated with the top differentially expressed genes in microglia included those related to proteostasis and immune modulation while those for astrocytes also included proteostasis, as well as stress response and metal ion homeostasis.  Inferred regulons generated from co-expression networks implicated distinct transcriptional mechanisms associated with pTau for the two cell types.  Data-driven sub-clustering revealed additional glial cellular heterogeneity.   Our work provides a new resource, highlighting both potential causal mechanisms and protective glial responses in AD. Overall design: Single-nuclei RNA-sequencing of microglia and astrocyte nuclei isolated post mortem from non-diseased control and neuropathologically-defined AD brains.