Cell Reports (Jul 2020)
Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models
- 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
Affiliations
- Ying-Wooi Wan
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurologic Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
- Rami Al-Ouran
- Jan and Dan Duncan Neurologic Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Carl G. Mangleburg
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurologic Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
- Thanneer M. Perumal
- Sage Bionetworks, Seattle, WA 98121, USA
- Tom V. Lee
- Jan and Dan Duncan Neurologic Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA
- Katherine Allison
- Jan and Dan Duncan Neurologic Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA
- Vivek Swarup
- Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA
- Cory C. Funk
- Institute for Systems Biology, Seattle, WA 98109, USA
- Chris Gaiteri
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
- Mariet Allen
- Mayo Clinic, Department of Neuroscience, Jacksonville, FL 32224, USA
- Minghui Wang
- Department of Genetics and Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Sarah M. Neuner
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
- Catherine C. Kaczorowski
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
- Vivek M. Philip
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
- Gareth R. Howell
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
- Heidi Martini-Stoica
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
- Hui Zheng
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
- Hongkang Mei
- Neuroscience DPU, Shanghai R&D, GlaxoSmithKline, Shanghai, China
- Xiaoyan Zhong
- Neuroscience DPU, Shanghai R&D, GlaxoSmithKline, Shanghai, China
- Jungwoo Wren Kim
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Valina L. Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin & Diana Helis Henry Medical Research Foundations, New Orleans, LA 70130, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Ted M. Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin & Diana Helis Henry Medical Research Foundations, New Orleans, LA 70130, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Ping-Chieh Pao
- The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Li-Huei Tsai
- The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Jean-Vianney Haure-Mirande
- Departments of Neurology and Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Michelle E. Ehrlich
- Department of Genetics and Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Departments of Neurology and Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Paramita Chakrabarty
- Evelyn F. and William L. McKnight Brain Institute, Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA
- Yona Levites
- Evelyn F. and William L. McKnight Brain Institute, Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA
- Xue Wang
- Mayo Clinic, Department of Neuroscience, Jacksonville, FL 32224, USA; Mayo Clinic, Department of Health Sciences Research, Jacksonville, FL 32224, USA
- Eric B. Dammer
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
- Gyan Srivastava
- Data & Statistical Sciences, AbbVie, Cambridge, MA, USA
- Sumit Mukherjee
- Sage Bionetworks, Seattle, WA 98121, USA
- Solveig K. Sieberts
- Sage Bionetworks, Seattle, WA 98121, USA
- Larsson Omberg
- Sage Bionetworks, Seattle, WA 98121, USA
- Kristen D. Dang
- Sage Bionetworks, Seattle, WA 98121, USA
- James A. Eddy
- Sage Bionetworks, Seattle, WA 98121, USA
- Phil Snyder
- Sage Bionetworks, Seattle, WA 98121, USA
- Yooree Chae
- Sage Bionetworks, Seattle, WA 98121, USA
- Sandeep Amberkar
- Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, S10 2HQ, UK; Molecular Oncology Lab, Cancer Research UK – Manchester Institute, The University of Manchester, Manchester, SK10 4TG, UK
- Wenbin Wei
- Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, S10 2HQ, UK; Department of Biosciences, Durham University, Durham, DH1 3LE, UK
- Winston Hide
- Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, S10 2HQ, UK; Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
- Christoph Preuss
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
- Ayla Ergun
- Translational Genome Sciences, Biogen, Cambridge, MA, USA
- Phillip J. Ebert
- Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
- David C. Airey
- Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
- Sara Mostafavi
- University of British Columbia, Vancouver, BC, Canada
- Lei Yu
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
- Hans-Ulrich Klein
- Center for Translational & Computational Neuroimmunology, Department of Neurology and Taub Institute for the Study of Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA; Cell Circuits Program, Broad Institute, Cambridge, MA 02142, USA
- Gregory W. Carter
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
- David A. Collier
- Eli Lilly & Company, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, UK
- Todd E. Golde
- Evelyn F. and William L. McKnight Brain Institute, Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA
- Allan I. Levey
- Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
- David A. Bennett
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
- Karol Estrada
- Translational Genome Sciences, Biogen, Cambridge, MA, USA
- T. Matthew Townsend
- Foundation Neuroscience Center, AbbVie, Cambridge, MA, USA
- Bin Zhang
- Department of Genetics and Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Eric Schadt
- Department of Genetics and Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Philip L. De Jager
- Center for Translational & Computational Neuroimmunology, Department of Neurology and Taub Institute for the Study of Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA; Cell Circuits Program, Broad Institute, Cambridge, MA 02142, USA
- Nathan D. Price
- Institute for Systems Biology, Seattle, WA 98109, USA
- Nilüfer Ertekin-Taner
- Mayo Clinic, Department of Neuroscience, Jacksonville, FL 32224, USA; Mayo Clinic, Department of Neurology, Jacksonville, FL 32224, USA
- Zhandong Liu
- Jan and Dan Duncan Neurologic Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Corresponding author
- Joshua M. Shulman
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurologic Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Corresponding author
- Lara M. Mangravite
- Sage Bionetworks, Seattle, WA 98121, USA; Corresponding author
- Benjamin A. Logsdon
- Sage Bionetworks, Seattle, WA 98121, USA; Corresponding author
- Journal volume & issue
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Vol. 32,
no. 2
p. 107908
Abstract
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.
