Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models

• Main Authors: Ying-Wooi Wan, Rami Al-Ouran, Carl G. Mangleburg, Thanneer M. Perumal, Tom V. Lee, Katherine Allison, Vivek Swarup, Cory C. Funk, Chris Gaiteri, Mariet Allen, Minghui Wang, Sarah M. Neuner, Catherine C. Kaczorowski, Vivek M. Philip, Gareth R. Howell, Heidi Martini-Stoica, Hui Zheng, Hongkang Mei, Xiaoyan Zhong, Jungwoo Wren Kim, Valina L. Dawson, Ted M. Dawson, Ping-Chieh Pao, Li-Huei Tsai, Jean-Vianney Haure-Mirande, Michelle E. Ehrlich, Paramita Chakrabarty, Yona Levites, Xue Wang, Eric B. Dammer, Gyan Srivastava, Sumit Mukherjee, Solveig K. Sieberts, Larsson Omberg, Kristen D. Dang, James A. Eddy, Phil Snyder, Yooree Chae, Sandeep Amberkar, Wenbin Wei, Winston Hide, Christoph Preuss, Ayla Ergun, Phillip J. Ebert, David C. Airey, Sara Mostafavi, Lei Yu, Hans-Ulrich Klein, Gregory W. Carter, David A. Collier, Todd E. Golde, Allan I. Levey, David A. Bennett, Karol Estrada, T. Matthew Townsend, Bin Zhang, Eric Schadt, Philip L. De Jager, Nathan D. Price, Nilüfer Ertekin-Taner, Zhandong Liu, Joshua M. Shulman, Lara M. Mangravite, Benjamin A. Logsdon
• Format: Article
• Language: English
• Published: Elsevier 2020-07-01
• Series: Cell Reports
• Subjects: Alzheimer's disease; transcriptome; RNA-seq; coexpression analysis; differential expression analysis; meta-analysis
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124720308895
• ISSN: 2211-1247

Summary: 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.