Temporal tracking of microglia activation in neurodegeneration at single-cell resolution

Abstract

A number of the genetic variants associated with an increased risk for Alzheimer’s disease (AD) in human genome-wide association studies (GWAS) are linked to genes with identified or putative roles in myeloid lineage cells, particularly in brain microglia, the “immune” cell of the brain. We recently carried out an epigenomic study to reveal that increased enhancer activity is associated with upregulated gene expression in AD mouse models and human postmortem AD brains. Nonetheless, much remains to be learned about the molecular changes underlying the response of microglia in the AD brain. Genome-wide transcriptional profiling in microglia has revealed wide-spread changes in gene expression in mouse models of AD. However, ensemble-based approaches measuring gene expression from bulk populations of microglia cells in AD brains can only report population averages that may not reflect the response of individual cells. Using single-cell RNA-sequencing we determined the transcriptome of individual microglia cells isolated from the hippocampus of a mouse model of severe neurodegeneration with AD-like phenotypes at multiple time points during progression of neurodegeneration. Our analysis identified novel disease stage-specific microglia cell states, revealed the trajectory of cellular reprogramming of microglia in response to neurodegeneration and uncovered the underlying transcriptional programs. Currently, our efforts are directed towards analyzing the transcriptomic heterogeneity of microglia isolated from human postmortem brain tissue of subjects with and without AD pathology.