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

Ying‐Wooi Wan(Baylor College of Medicine), Rami Al‐Ouran(Baylor College of Medicine), Carl Grant Mangleburg(Baylor College of Medicine), Thanneer M. Perumal(Sage Bionetworks), Tom V. Lee(Baylor College of Medicine), Katherine Allison(Baylor College of Medicine), Vivek Swarup(University of California, Irvine), Cory C. Funk(Institute for Systems Biology), Chris Gaiteri(Rush University Medical Center), Mariet Allen(Mayo Clinic in Florida), Minghui Wang(Icahn School of Medicine at Mount Sinai), Sarah M. Neuner(Jackson Laboratory), Catherine C. Kaczorowski(Jackson Laboratory), Vivek M. Philip(Jackson Laboratory), Gareth R. Howell(Jackson Laboratory), Heidi Martini‐Stoica(Baylor College of Medicine), Hui Zheng(Baylor College of Medicine), Hongkang Mei(GlaxoSmithKline (China)), Xiaoyan Zhong(GlaxoSmithKline (China)), Jungwoo Wren Kim(Johns Hopkins University), Valina L. Dawson(Johns Hopkins University), Ted M. Dawson(Johns Hopkins University), Ping‐Chieh Pao(Broad Institute), Li‐Huei Tsai(Broad Institute), Jean‐Vianney Haure‐Mirande(Icahn School of Medicine at Mount Sinai), Michelle E. Ehrlich(Icahn School of Medicine at Mount Sinai), Paramita Chakrabarty(University of Florida), Yona Levites(University of Florida), Xue Wang(Jacksonville College), Eric B. Dammer(Emory University), Gyan Srivastava(AbbVie (United States)), Sumit Mukherjee(Sage Bionetworks), Solveig K. Sieberts(Sage Bionetworks), Larsson Omberg(Sage Bionetworks), Kristen K. Dang(Sage Bionetworks), James A. Eddy(Sage Bionetworks), Phil Snyder(Sage Bionetworks), Yooree Chae(Sage Bionetworks), Sandeep Amberkar(University of Manchester), Wenbin Wei(Durham University), Winston Hide(Beth Israel Deaconess Medical Center), Christoph Preuß(Jackson Laboratory), Ayla Ergün(Biogen (United States)), Phillip J. Ebert(Eli Lilly (United States)), David Airey(Eli Lilly (United States)), Sara Mostafavi(University of British Columbia), Lei Yu(Rush University Medical Center), Hans‐Ulrich Klein(Broad Institute), Gregory W. Carter(Jackson Laboratory), David Collier(Eli Lilly (United Kingdom)), Todd E. Golde(University of Florida), Allan I. Levey(Emory University), David A. Bennett(Rush University Medical Center), Karol Estrada(Biogen (United States)), T. Matthew Townsend(AbbVie (United States)), Bin Zhang(Icahn School of Medicine at Mount Sinai), Eric E. Schadt(Icahn School of Medicine at Mount Sinai), Philip L. De Jager(Broad Institute), Nathan D. Price(Institute for Systems Biology), Nilüfer Ertekin‐Taner(Jacksonville College), Zhandong Liu(Baylor College of Medicine), Joshua M. Shulman(Baylor College of Medicine), Lara M. Mangravite(Sage Bionetworks), Benjamin A. Logsdon(Sage Bionetworks)
Cell Reports
July 1, 2020
10.1016/j.celrep.2020.107908
Cited by 328Open Access
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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.

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