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

doi:10.1038/s41593-019-0539-4

. 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

Alexandra Grubman^#^{1

2

3}, Gabriel Chew^#⁴, John F Ouyang^#⁴, Guizhi Sun^{1

2

3}, Xin Yi Choo^{1

2

3

5}, Catriona McLean⁶, Rebecca K Simmons^{7

8}, Sam Buckberry^{7

8}, Dulce B Vargas-Landin^{7

8}, Daniel Poppe^{7

8}, Jahnvi Pflueger^{7

8}, Ryan Lister^{7

8}, Owen J L Rackham⁹, Enrico Petretto¹⁰, Jose M Polo^{11

12

13}

Affiliations

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.

^# Contributed equally.

PMID: 31768052
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

Alexandra Grubman et al. Nat Neurosci. 2019 Dec.

. 2019 Dec;22(12):2087-2097.

doi: 10.1038/s41593-019-0539-4.

Authors

Affiliations

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.

^# Contributed equally.

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

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.

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Comment in

Single-cell atlas maps cell-specific gene changes in Alzheimer disease.
Fyfe I. Fyfe I. Nat Rev Neurol. 2020 Jan;16(1):1. doi: 10.1038/s41582-019-0300-3. Nat Rev Neurol. 2020. PMID: 31827266 No abstract available.

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References

1. Huang, K.-L. et al. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat. Neurosci. 20, 1052–1061 (2017). - PubMed - PMC
1. Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013). - PubMed - PMC
1. Zhang, B. et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153, 707–720 (2013). - PubMed - PMC
1. Füger, P. et al. Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging. Nat. Neurosci. 20, 1371–1376 (2017). - PubMed
1. Whitehouse, P. J. et al. Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science 215, 1237–1239 (1982). - PubMed

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[1] Huang, K.-L. et al. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat. Neurosci. 20, 1052–1061 (2017). - PubMed - PMC

[2] Huang, K.-L. et al. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat. Neurosci. 20, 1052–1061 (2017). - PubMed - PMC

[3] Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013). - PubMed - PMC

[4] Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013). - PubMed - PMC

[5] Zhang, B. et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153, 707–720 (2013). - PubMed - PMC

[6] Zhang, B. et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153, 707–720 (2013). - PubMed - PMC

[7] Füger, P. et al. Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging. Nat. Neurosci. 20, 1371–1376 (2017). - PubMed

[8] Füger, P. et al. Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging. Nat. Neurosci. 20, 1371–1376 (2017). - PubMed

[9] Whitehouse, P. J. et al. Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science 215, 1237–1239 (1982). - PubMed

[10] Whitehouse, P. J. et al. Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science 215, 1237–1239 (1982). - PubMed

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

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

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