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Title: A transcriptomic atlas of aged human microglia

Abstract

With a rapidly aging global human population, finding a cure for late onset neurodegenerative diseases has become an urgent enterprise. However, these efforts are hindered by the lack of understanding of what constitutes the phenotype of aged human microglia—the cell type that has been strongly implicated by genetic studies in the pathogenesis of age-related neurodegenerative disease. Here, we establish the set of genes that is preferentially expressed by microglia in the aged human brain. This HuMi_Aged gene set captures a unique phenotype, which we confirm at the protein level. Furthermore, we find this gene set to be enriched in susceptibility genes for Alzheimer’s disease and multiple sclerosis, to be increased with advancing age, and to be reduced by the protective APOEe2 haplotype. APOEe4 has no effect. These findings confirm the existence of an aging-related microglial phenotype in the aged human brain and its involvement in the pathological processes associated with brain aging.

Authors:
 [1]; ORCiD logo [2];  [3]; ORCiD logo [4];  [4];  [5]; ORCiD logo [6];  [6];  [4]; ORCiD logo [5];  [1];  [7];  [5];  [5];  [1]; ORCiD logo [6];  [8];  [8]; ORCiD logo [1];  [1]
  1. Columbia Univ. Medical Center, New York City, NY (United States); Broad Inst., Cambridge, MA (United States)
  2. Univ. of Sydney, NSW (Australia)
  3. Broad Inst., Cambridge, MA (United States); Massachusetts General Hospital, Boston, MA (United States)
  4. Broad Inst., Cambridge, MA (United States)
  5. Brigham and Women's Hospital (Harvard Medical School), Boston, MA (United States)
  6. Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
  7. Columbia Univ. Medical Center, New York City, NY (United States)
  8. Rush Univ. Medical Center, Chicago, IL (United States)
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1490325
Report Number(s):
PNNL-SA-134273
Journal ID: ISSN 2041-1723
Grant/Contract Number:  
AC05-76RL01830
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Olah, Marta, Patrick, Ellis, Villani, Alexandra-Chloe, Xu, Jishu, White, Charles C., Ryan, Katie J., Piehowski, Paul, Kapasi, Alifiya, Nejad, Parham, Cimpean, Maria, Connor, Sarah, Yung, Christina J., Frangieh, Michael, McHenry, Allison, Elyaman, Wassim, Petyuk, Vlad, Schneider, Julie A., Bennett, David A., De Jager, Philip L., and Bradshaw, Elizabeth M. A transcriptomic atlas of aged human microglia. United States: N. p., 2018. Web. doi:10.1038/s41467-018-02926-5.
Olah, Marta, Patrick, Ellis, Villani, Alexandra-Chloe, Xu, Jishu, White, Charles C., Ryan, Katie J., Piehowski, Paul, Kapasi, Alifiya, Nejad, Parham, Cimpean, Maria, Connor, Sarah, Yung, Christina J., Frangieh, Michael, McHenry, Allison, Elyaman, Wassim, Petyuk, Vlad, Schneider, Julie A., Bennett, David A., De Jager, Philip L., & Bradshaw, Elizabeth M. A transcriptomic atlas of aged human microglia. United States. doi:10.1038/s41467-018-02926-5.
Olah, Marta, Patrick, Ellis, Villani, Alexandra-Chloe, Xu, Jishu, White, Charles C., Ryan, Katie J., Piehowski, Paul, Kapasi, Alifiya, Nejad, Parham, Cimpean, Maria, Connor, Sarah, Yung, Christina J., Frangieh, Michael, McHenry, Allison, Elyaman, Wassim, Petyuk, Vlad, Schneider, Julie A., Bennett, David A., De Jager, Philip L., and Bradshaw, Elizabeth M. Wed . "A transcriptomic atlas of aged human microglia". United States. doi:10.1038/s41467-018-02926-5. https://www.osti.gov/servlets/purl/1490325.
@article{osti_1490325,
title = {A transcriptomic atlas of aged human microglia},
author = {Olah, Marta and Patrick, Ellis and Villani, Alexandra-Chloe and Xu, Jishu and White, Charles C. and Ryan, Katie J. and Piehowski, Paul and Kapasi, Alifiya and Nejad, Parham and Cimpean, Maria and Connor, Sarah and Yung, Christina J. and Frangieh, Michael and McHenry, Allison and Elyaman, Wassim and Petyuk, Vlad and Schneider, Julie A. and Bennett, David A. and De Jager, Philip L. and Bradshaw, Elizabeth M.},
abstractNote = {With a rapidly aging global human population, finding a cure for late onset neurodegenerative diseases has become an urgent enterprise. However, these efforts are hindered by the lack of understanding of what constitutes the phenotype of aged human microglia—the cell type that has been strongly implicated by genetic studies in the pathogenesis of age-related neurodegenerative disease. Here, we establish the set of genes that is preferentially expressed by microglia in the aged human brain. This HuMi_Aged gene set captures a unique phenotype, which we confirm at the protein level. Furthermore, we find this gene set to be enriched in susceptibility genes for Alzheimer’s disease and multiple sclerosis, to be increased with advancing age, and to be reduced by the protective APOEe2 haplotype. APOEe4 has no effect. These findings confirm the existence of an aging-related microglial phenotype in the aged human brain and its involvement in the pathological processes associated with brain aging.},
doi = {10.1038/s41467-018-02926-5},
journal = {Nature Communications},
number = 1,
volume = 9,
place = {United States},
year = {2018},
month = {2}
}

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Cited by: 18 works
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Figures / Tables:

Fig. 1 Fig. 1: The HuMi_Aged and its relationship to genetic risk of AD. a Scatter plot depicting the distribution of gene expression values between the bulk DLPFC (N= 540) and the isolated microglia (N= 10). Each dot represents a gene. The X and the Y axes show normalized expression values. Onemore » thousand fifty four genes have been identified to be preferentially expressed by microglia (based on the differences in gene expression between the isolated microglia and the bulk cortical tissue, FC > 4) in the aged human brain (dark blue dots). This set of genes has been coined the HuMi_Aged gene set. The HuMi_Aged gene set contained many of the previously established microglia markers in the brain (black dots), such as CD74, CX3CR1, P2RY12, TREM2 or GPR34. b Scatter plot showing the distribution of AD risk genes (black dots) in the transcriptomic universe defined by the bulk cortical and the microglial RNA-Sequencing datasets. Each dot represents a gene. The X and the Y axes show normalized expression values. By using an overrepresentation test, the HuMi_Aged gene set (blue dots) was found to be significantly enriched in Alzheimer’s disease risk genes (black dots; enrichment p-value = 4.1e-05). The HuMi_Aged included AD risk genes, such as CD33, TREM2, INPP5D, APOC1 or SCIMP, while other AD risk genes (e.g., BIN1 or TREML2) were found to be not specific to microglia in the aged brain. c APOE ε2 was associated with reduced expression of HuMi_Aged in the bulk tissue level data (N = 540). DLPFC dorsolateral prefrontal cortex, FC fold change« less

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