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Meta-analysis of the Alzheimer’s disease human brain transcriptome and functional dissection in mouse models.

Wan, Ying-Wooi and Al-Ouran, Rami and Mangleburg, Carl G. and Perumal, Thanneer M. and Lee, Tom V. and Allison, Katherine and Swarup, Vivek and Funk, Cory C. and Gaiteri, Chris and Allen, Mariet and Wang, Minghui and Neuner, Sarah M. and Kaczorowski, Catherine C. and Philip, Vivek M. and Howell, Gareth R. and Martini-Stoica, Heidi and Zheng, Hui and Mei, Hongkang and Zhong, Xiaoyan and Kim, Jungwoo Wren and Dawson, Valina L. and Dawson, Ted M. and Pao, Ping-Chieh and Tsai, Li-Huei and Haure-Mirande, Jean-Vianney and Ehrlich, Michelle E. and Chakrabarty, Paramita and Levites, Yona and Wang, Xue and Dammer, Eric B. and Srivastava, Gyan and Mukherjee, Sumit and Sieberts, Solveig K. and Omberg, Larsson and Dang, Kristen D. and Eddy, James A. and Snyder, Phil and Chae, Yooree and Amberkar, Sandeep and Wei, Wenbin and Hide, Winston and Preuss, Christoph and Ergun, Ayla and Ebert, Phillip J. and Airey, David C. and Mostafavi, Sara and Yu, Lei and Klein, Hans-Ulrich and Carter, Gregory W. and Collier, David A. and Golde, Todd E. and Levey, Allan I. and Bennett, David A. and Estrada, Karol and Townsend, T. Matthew and Zhang, Bin and Schadt, Eric and De Jager, Philip L. and Price, Nathan D. and Ertekin-Taner, Nilüfer and Liu, Zhandong and Shulman, Joshua M. and Mangravite, Lara M. and Logsdon, Benjamin A. (2020) 'Meta-analysis of the Alzheimer’s disease human brain transcriptome and functional dissection in mouse models.', Cell reports., 32 (2). p. 107908.

Abstract

We present a consensus atlas of the human brain transcriptome in Alzheimer’s disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington’s disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.

Item Type:Article
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Available under License - Creative Commons Attribution.
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Status:Peer-reviewed
Publisher Web site:https://doi.org/10.1016/j.celrep.2020.107908
Publisher statement:© 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Date accepted:24 June 2020
Date deposited:22 July 2020
Date of first online publication:14 July 2020
Date first made open access:22 July 2020

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