A single-cell atlas of entorhinal cortex from individuals with Alzheimer's disease reveals cell-type-specific gene expression regulation
Grubman, Alexandra Chew, Gabriel OUYANG FENGCONG JOHN Sun, Guizhi Choo, Xin Yi McLean, Catriona Simmons, Rebecca K Buckberry, Sam Vargas-Landin, Dulce B Poppe, Daniel
Grubman, Alexandra
Chew, Gabriel
Sun, Guizhi
Choo, Xin Yi
McLean, Catriona
Simmons, Rebecca K
Buckberry, Sam
Vargas-Landin, Dulce B
Poppe, Daniel
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Alternative Title
Abstract
There is currently little information available about how individual cell types contribute to Alzheimer’s disease. Here we applied single-nucleus RNA sequencing to entorhinal cortex samples from control and Alzheimer’s disease brains (n = 6 per group), yielding a total of 13,214 high-quality nuclei. We detail cell-type-specific gene expression patterns, unveiling how transcriptional changes in specific cell subpopulations are associated with Alzheimer’s disease. We report that the Alzheimer’s disease risk gene APOE is specifically repressed in Alzheimer’s disease oligodendrocyte progenitor cells and astrocyte subpopulations and upregulated in an Alzheimer’s disease-specific microglial subopulation. Integrating transcription factor regulatory modules with Alzheimer’s disease risk loci revealed drivers of cell-type-specific state transitions towards Alzheimer’s disease. For example, transcription factor EB, a master regulator of lysosomal function, regulates multiple disease genes in a specific Alzheimer’s disease astrocyte subpopulation. These results provide insights into the coordinated control of Alzheimer’s disease risk genes and their cell-type-specific contribution to disease susceptibility. These results are available at http://adsn.ddnetbio.com.
Keywords
Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, RNA-SEQ, COGNITIVE DECLINE, MYELIN BREAKDOWN, R PACKAGE, MICROGLIA, BIN1, ASSOCIATION, INHIBITION, DIVERSITY, COMPLEX
Source Title
NATURE NEUROSCIENCE
Publisher
NATURE PUBLISHING GROUP
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Date
2019-12-01
DOI
10.1038/s41593-019-0539-4
Type
Article