Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses

• Published in: Nature communications Vol. 7; no. 1; pp. 11295 - 16
• Main Authors: Srinivasan, Karpagam, Friedman, Brad A., Larson, Jessica L., Lauffer, Benjamin E., Goldstein, Leonard D., Appling, Laurie L., Borneo, Jovencio, Poon, Chungkee, Ho, Terence, Cai, Fang, Steiner, Pascal, van der Brug, Marcel P., Modrusan, Zora, Kaminker, Joshua S., Hansen, David V.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.04.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 38/39; 38/61; 38/62; 38/77; 38/90; 38/91; 631/337/572; 631/378/1689/364; 631/378/371; 64/60; Adult; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Animals; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - pathology; Brain; Cerebellum - drug effects; Cerebellum - metabolism; Cerebellum - pathology; Disease; Disease Models, Animal; Endotoxemia - chemically induced; Endotoxemia - genetics; Endotoxemia - metabolism; Endotoxemia - pathology; Frontal Lobe - drug effects; Frontal Lobe - metabolism; Frontal Lobe - pathology; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Humanities and Social Sciences; Humans; Lipopolysaccharides - pharmacology; Methods; Mice; Microglia - drug effects; Microglia - metabolism; Microglia - pathology; multidisciplinary; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Organ Specificity; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; Science; Science (multidisciplinary); Sequence Analysis, RNA; Tissues; Transcription, Genetic; Transcriptome; United States > US; South San Francisco California; California
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11295

A common approach to understanding neurodegenerative disease is comparing gene expression in diseased versus healthy tissues. We illustrate that expression profiles derived from whole tissue RNA highly reflect the degenerating tissues’ altered cellular composition, not necessarily transcriptional regulation. To accurately understand transcriptional changes that accompany neuropathology, we acutely purify neurons, astrocytes and microglia from single adult mouse brains and analyse their transcriptomes by RNA sequencing. Using peripheral endotoxemia to establish the method, we reveal highly specific transcriptional responses and altered RNA processing in each cell type, with Tnfr1 required for the astrocytic response. Extending the method to an Alzheimer’s disease model, we confirm that transcriptomic changes observed in whole tissue are driven primarily by cell type composition, not transcriptional regulation, and identify hundreds of cell type-specific changes undetected in whole tissue RNA. Applying similar methods to additional models and patient tissues will transform our understanding of aberrant gene expression in neurological disease. Whole tissue RNA profiling can help identify altered molecular pathways underlying neurodegenerative disease, but often masks cell type-specific transcriptional changes. Here, the authors compare transcriptomes of neurons, astrocytes, and microglia from Alzheimer's disease model brains and identify hundreds of cell-type specific changes.