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Nat Neurosci. 2019 Dec;22(12):2087-2097. doi: 10.1038/s41593-019-0539-4.

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

Author information

1
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
2
Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, Victoria, Australia.
3
Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
4
Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore, Singapore.
5
Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
6
Victorian Brain Bank, Florey Institute of Neurosciences, Parkville, Victoria, Australia.
7
ARC Center of Excellence in Plant Energy Biology, The University of Western Australia, Perth, Western Australia, Australia.
8
The Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia.
9
Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore, Singapore. owen.rackham@duke-nus.edu.sg.
10
Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore, Singapore. enrico.petretto@duke-nus.edu.sg.
11
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia. jose.polo@monash.edu.
12
Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, Victoria, Australia. jose.polo@monash.edu.
13
Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. jose.polo@monash.edu.

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 (nā€‰=ā€‰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.

PMID:
31768052
DOI:
10.1038/s41593-019-0539-4

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