A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation

Alexandra Grubman, Gabriel Chew, John F. Ouyang, Guizhi Sun, Xin Yi Choo, Catriona McLean, Rebecca K. Simmons, Sam Buckberry, Dulce B. Vargas-Landin, Daniel Poppe, Jahnvi Pflueger, Ryan Lister, Owen J.L. Rackham, Enrico Petretto, Jose M. Polo

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2087-2097
Number of pages11
JournalNature Neuroscience
Volume22
Issue number12
DOIs
Publication statusPublished - Dec 2019

Keywords

  • Alzheimer's Disease
  • gene expression profiling
  • gene regulatory networks
  • transcriptomics

Cite this

Grubman, A., Chew, G., Ouyang, J. F., Sun, G., Choo, X. Y., McLean, C., Simmons, R. K., Buckberry, S., Vargas-Landin, D. B., Poppe, D., Pflueger, J., Lister, R., Rackham, O. J. L., Petretto, E., & Polo, J. M. (2019). A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nature Neuroscience, 22(12), 2087-2097. https://doi.org/10.1038/s41593-019-0539-4