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Sex-Stratified Single-Cell RNA-Seq Analysis Identifies Sex-Specific and Cell Type-Specific Transcriptional Responses in Alzheimer’s Disease Across Two Brain Regions
Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder that disproportionately affects women. Since neural anatomy and disease pathophysiology differ by sex, investigating sex-specific mechanisms in AD pathophysiology can inform new therapeutic approaches for both sexes. Previous bulk hu...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8786804/ https://www.ncbi.nlm.nih.gov/pubmed/34669146 http://dx.doi.org/10.1007/s12035-021-02591-8 |
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author | Belonwu, Stella A. Li, Yaqiao Bunis, Daniel Rao, Arjun Arkal Solsberg, Caroline Warly Tang, Alice Fragiadakis, Gabriela K. Dubal, Dena B. Oskotsky, Tomiko Sirota, Marina |
author_facet | Belonwu, Stella A. Li, Yaqiao Bunis, Daniel Rao, Arjun Arkal Solsberg, Caroline Warly Tang, Alice Fragiadakis, Gabriela K. Dubal, Dena B. Oskotsky, Tomiko Sirota, Marina |
author_sort | Belonwu, Stella A. |
collection | PubMed |
description | Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder that disproportionately affects women. Since neural anatomy and disease pathophysiology differ by sex, investigating sex-specific mechanisms in AD pathophysiology can inform new therapeutic approaches for both sexes. Previous bulk human brain RNA sequencing studies have revealed sex differences in dysregulated molecular pathways related to energy production, neuronal function, and immune response; however, the sex differences in disease mechanisms are yet to be examined comprehensively on a single-cell level. We leveraged nearly 74,000 cells from human prefrontal and entorhinal cortex samples from the first two publicly available single-cell RNA sequencing AD datasets to perform a case versus control sex-stratified differential gene expression analysis and pathway network enrichment in a cell type-specific manner for each brain region. Our examination at the single-cell level revealed sex differences in AD prominently in glial cells of the prefrontal cortex. In the entorhinal cortex, we observed the same genes and networks to be perturbed in opposing directions between sexes in AD relative to healthy state. Our findings contribute to growing evidence of sex differences in AD-related transcriptomic changes, which can fuel the development of therapies that may prove more effective at reversing AD pathophysiology. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-021-02591-8. |
format | Online Article Text |
id | pubmed-8786804 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-87868042022-02-02 Sex-Stratified Single-Cell RNA-Seq Analysis Identifies Sex-Specific and Cell Type-Specific Transcriptional Responses in Alzheimer’s Disease Across Two Brain Regions Belonwu, Stella A. Li, Yaqiao Bunis, Daniel Rao, Arjun Arkal Solsberg, Caroline Warly Tang, Alice Fragiadakis, Gabriela K. Dubal, Dena B. Oskotsky, Tomiko Sirota, Marina Mol Neurobiol Article Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder that disproportionately affects women. Since neural anatomy and disease pathophysiology differ by sex, investigating sex-specific mechanisms in AD pathophysiology can inform new therapeutic approaches for both sexes. Previous bulk human brain RNA sequencing studies have revealed sex differences in dysregulated molecular pathways related to energy production, neuronal function, and immune response; however, the sex differences in disease mechanisms are yet to be examined comprehensively on a single-cell level. We leveraged nearly 74,000 cells from human prefrontal and entorhinal cortex samples from the first two publicly available single-cell RNA sequencing AD datasets to perform a case versus control sex-stratified differential gene expression analysis and pathway network enrichment in a cell type-specific manner for each brain region. Our examination at the single-cell level revealed sex differences in AD prominently in glial cells of the prefrontal cortex. In the entorhinal cortex, we observed the same genes and networks to be perturbed in opposing directions between sexes in AD relative to healthy state. Our findings contribute to growing evidence of sex differences in AD-related transcriptomic changes, which can fuel the development of therapies that may prove more effective at reversing AD pathophysiology. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-021-02591-8. Springer US 2021-10-20 2022 /pmc/articles/PMC8786804/ /pubmed/34669146 http://dx.doi.org/10.1007/s12035-021-02591-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Belonwu, Stella A. Li, Yaqiao Bunis, Daniel Rao, Arjun Arkal Solsberg, Caroline Warly Tang, Alice Fragiadakis, Gabriela K. Dubal, Dena B. Oskotsky, Tomiko Sirota, Marina Sex-Stratified Single-Cell RNA-Seq Analysis Identifies Sex-Specific and Cell Type-Specific Transcriptional Responses in Alzheimer’s Disease Across Two Brain Regions |
title | Sex-Stratified Single-Cell RNA-Seq Analysis Identifies Sex-Specific and Cell Type-Specific Transcriptional Responses in Alzheimer’s Disease Across Two Brain Regions |
title_full | Sex-Stratified Single-Cell RNA-Seq Analysis Identifies Sex-Specific and Cell Type-Specific Transcriptional Responses in Alzheimer’s Disease Across Two Brain Regions |
title_fullStr | Sex-Stratified Single-Cell RNA-Seq Analysis Identifies Sex-Specific and Cell Type-Specific Transcriptional Responses in Alzheimer’s Disease Across Two Brain Regions |
title_full_unstemmed | Sex-Stratified Single-Cell RNA-Seq Analysis Identifies Sex-Specific and Cell Type-Specific Transcriptional Responses in Alzheimer’s Disease Across Two Brain Regions |
title_short | Sex-Stratified Single-Cell RNA-Seq Analysis Identifies Sex-Specific and Cell Type-Specific Transcriptional Responses in Alzheimer’s Disease Across Two Brain Regions |
title_sort | sex-stratified single-cell rna-seq analysis identifies sex-specific and cell type-specific transcriptional responses in alzheimer’s disease across two brain regions |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8786804/ https://www.ncbi.nlm.nih.gov/pubmed/34669146 http://dx.doi.org/10.1007/s12035-021-02591-8 |
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