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; Accelerating Medicines Partnership-Alzheimer’s Disease Consortium; 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

doi:10.1016/j.celrep.2020.107908

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

Cell Rep. 2020 Jul 14;32(2):107908. doi: 10.1016/j.celrep.2020.107908.

Authors

Ying-Wooi Wan¹, Rami Al-Ouran², Carl G Mangleburg¹, Thanneer M Perumal³, Tom V Lee⁴, Katherine Allison⁴, Vivek Swarup⁵, Cory C Funk⁶, Chris Gaiteri⁷, Mariet Allen⁸, Minghui Wang⁹, Sarah M Neuner¹⁰, Catherine C Kaczorowski¹⁰, Vivek M Philip¹⁰, Gareth R Howell¹⁰, Heidi Martini-Stoica¹¹, Hui Zheng¹², Hongkang Mei¹³, Xiaoyan Zhong¹³, Jungwoo Wren Kim¹⁴, Valina L Dawson¹⁵, Ted M Dawson¹⁶, Ping-Chieh Pao¹⁷, Li-Huei Tsai¹⁷, Jean-Vianney Haure-Mirande¹⁸, Michelle E Ehrlich¹⁹, Paramita Chakrabarty²⁰, Yona Levites²⁰, Xue Wang²¹, Eric B Dammer²², Gyan Srivastava²³, Sumit Mukherjee³, Solveig K Sieberts³, Larsson Omberg³, Kristen D Dang³, James A Eddy³, Phil Snyder³, Yooree Chae³, Sandeep Amberkar²⁴, Wenbin Wei²⁵, Winston Hide²⁶, Christoph Preuss¹⁰, Ayla Ergun²⁷, Phillip J Ebert²⁸, David C Airey²⁸, Sara Mostafavi²⁹, Lei Yu⁷, Hans-Ulrich Klein³⁰; Accelerating Medicines Partnership-Alzheimer’s Disease Consortium³¹; Gregory W Carter¹⁰, David A Collier³², Todd E Golde²⁰, Allan I Levey³³, David A Bennett⁷, Karol Estrada²⁷, T Matthew Townsend³⁴, Bin Zhang⁹, Eric Schadt⁹, Philip L De Jager³⁰, Nathan D Price⁶, Nilüfer Ertekin-Taner³⁵, Zhandong Liu³⁶, Joshua M Shulman³⁷, Lara M Mangravite³⁸, Benjamin A Logsdon³⁹

Affiliations

¹ 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.
² 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.
³ Sage Bionetworks, Seattle, WA 98121, USA.
⁴ 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.
⁵ Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
⁶ Institute for Systems Biology, Seattle, WA 98109, USA.
⁷ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁸ Mayo Clinic, Department of Neuroscience, Jacksonville, FL 32224, USA.
⁹ 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.
¹⁰ The Jackson Laboratory, Bar Harbor, ME 04609, USA.
¹¹ Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
¹² 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.
¹³ Neuroscience DPU, Shanghai R&D, GlaxoSmithKline, Shanghai, China.
¹⁴ 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.
¹⁵ 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.
¹⁶ 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.
¹⁷ 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.
¹⁸ Departments of Neurology and Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
¹⁹ 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.
²⁰ 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.
²¹ Mayo Clinic, Department of Neuroscience, Jacksonville, FL 32224, USA; Mayo Clinic, Department of Health Sciences Research, Jacksonville, FL 32224, USA.
²² Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
²³ Data & Statistical Sciences, AbbVie, Cambridge, MA, USA.
²⁴ 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.
²⁵ Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, S10 2HQ, UK; Department of Biosciences, Durham University, Durham, DH1 3LE, UK.
²⁶ Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, S10 2HQ, UK; Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
²⁷ Translational Genome Sciences, Biogen, Cambridge, MA, USA.
²⁸ Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
²⁹ University of British Columbia, Vancouver, BC, Canada.
³⁰ 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.
³¹ Full consortium author list available at http://doi.org/10.7303/syn17114455.
³² Eli Lilly & Company, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, UK.
³³ Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
³⁴ Foundation Neuroscience Center, AbbVie, Cambridge, MA, USA.
³⁵ Mayo Clinic, Department of Neuroscience, Jacksonville, FL 32224, USA; Mayo Clinic, Department of Neurology, Jacksonville, FL 32224, USA.
³⁶ 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. Electronic address: zhandonl@bcm.edu.
³⁷ 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. Electronic address: joshua.shulman@bcm.edu.
³⁸ Sage Bionetworks, Seattle, WA 98121, USA. Electronic address: lara.mangravite@sagebionetworks.org.
³⁹ Sage Bionetworks, Seattle, WA 98121, USA. Electronic address: ben.logsdon@sagebionetworks.org.

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.

Keywords: Alzheimer's disease; RNA-seq; aging; coexpression analysis; differential expression analysis; meta-analysis; mouse models; neuroinflammation; transcriptome.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alzheimer Disease / genetics*
Animals
Brain / metabolism*
Brain / pathology*
Case-Control Studies
Disease Models, Animal
Female
Gene Expression Profiling
Gene Expression Regulation
Gene Regulatory Networks
Humans
Male
Mice
Sex Characteristics
Species Specificity
Transcription, Genetic
Transcriptome / genetics*

Abstract

Publication types

MeSH terms

Grants and funding