Deciphering transcriptomic changes in human brains during neurodegeneration at single-cell resolution
Hansruedi Mathys1,2, Jose Davila Velderrain3,4, Shahin Mohammadi3,4, Fan Gao1,2, Zhuyu Peng1,2, Thorvald Andreassen5, David A. Bennett6, Manolis Kellis3,4, and Li-Huei Tsai1,2,3 1Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; 2Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; 3Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA; 4MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, Massachusetts 02139, USA; 5McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; 6Rush Alzheimer Disease Center, Rush University Medical Center, Chicago, IL, USA 60612
Transcriptomic analyses of human postmortem Alzheimer's disease (AD) brains have revealed global changes in gene expression patterns that are characterized by the downregulation of genes associated with synaptic function, learning and memory, and the upregulation of adaptive as well as innate immune response genes. However, since the brain is a complex system built from many different functionally specialized cell types, ensemble-based approaches measuring gene expression from bulk populations of cells can only report population averages that may not reflect the responses of individual cells. Recent advances in high-throughput single-cell RNA sequencing technology now allow us to determine how the different cell types and their subclasses in the brain are affected by the disease. We used single-cell RNA-sequencing to determine the phenotypic heterogeneity of microglia during the progression of the disease in a mouse model of severe neurodegeneration. In this model we identified multiple disease stage-specific microglia cell states that are not present in the healthy brain. We found that the early response of microglia to neuronal insult is characterized by a marked increase in proliferation. In contrast, in later stages of neurodegeneration, microglia upregulate immune response genes. Specifically, we identified two molecularly distinct reactive microglia phenotypes that are typified by modules of co- regulated type I and type II interferon response genes, respectively. In summary, our work identified 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 different cell types isolated from human postmortem brain tissue of subjects with and without AD pathology.