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

Accelerating Medicines Partnership-Alzheimer's Disease Consortium

doi:10.1016/j.celrep.2020.107908

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

Accelerating Medicines Partnership-Alzheimer's Disease Consortium

School of Medicine

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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.

Original language	English (US)
Article number	107908
Journal	Cell Reports
Volume	32
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2020.107908
State	Published - Jul 14 2020

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2020.107908

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@article{46fa946240f544f596ea517830c90b26,

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

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",

author = "{Accelerating Medicines Partnership-Alzheimer's Disease Consortium} and Wan, {Ying Wooi} and Rami Al-Ouran and Mangleburg, {Carl G.} and Perumal, {Thanneer M.} and Lee, {Tom V.} and Katherine Allison and Vivek Swarup and Funk, {Cory C.} and Chris Gaiteri and Mariet Allen and Minghui Wang and Neuner, {Sarah M.} and Kaczorowski, {Catherine C.} and Philip, {Vivek M.} and Howell, {Gareth R.} and Heidi Martini-Stoica and Hui Zheng and Hongkang Mei and Xiaoyan Zhong 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 Paramita Chakrabarty and Yona Levites and Xue Wang and Dammer, {Eric B.} and Gyan Srivastava and Sumit Mukherjee and Sieberts, {Solveig K.} and Larsson Omberg and Dang, {Kristen D.} and Eddy, {James A.} and Phil Snyder and Yooree Chae and Sandeep Amberkar and Wenbin Wei and Winston Hide and Christoph Preuss and Ayla Ergun and Ebert, {Phillip J.} and Airey, {David C.} and Sara Mostafavi and Lei Yu and Klein, {Hans Ulrich} and Carter, {Gregory W.} and Price, {Nathan D.}",

note = "Publisher Copyright: {\textcopyright} 2020 The Authors",

year = "2020",

month = jul,

day = "14",

doi = "10.1016/j.celrep.2020.107908",

language = "English (US)",

volume = "32",

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T1 - Meta-Analysis of the Alzheimer's Disease Human Brain Transcriptome and Functional Dissection in Mouse Models

AU - Accelerating Medicines Partnership-Alzheimer's Disease Consortium

AU - Wan, Ying Wooi

AU - Al-Ouran, Rami

AU - Mangleburg, Carl G.

AU - Perumal, Thanneer M.

AU - Lee, Tom V.

AU - Allison, Katherine

AU - Swarup, Vivek

AU - Funk, Cory C.

AU - Gaiteri, Chris

AU - Allen, Mariet

AU - Wang, Minghui

AU - Neuner, Sarah M.

AU - Kaczorowski, Catherine C.

AU - Philip, Vivek M.

AU - Howell, Gareth R.

AU - Martini-Stoica, Heidi

AU - Zheng, Hui

AU - Mei, Hongkang

AU - Zhong, Xiaoyan

AU - Kim, Jungwoo Wren

AU - Dawson, Valina L.

AU - Dawson, Ted M.

AU - Pao, Ping Chieh

AU - Tsai, Li Huei

AU - Haure-Mirande, Jean Vianney

AU - Ehrlich, Michelle E.

AU - Chakrabarty, Paramita

AU - Levites, Yona

AU - Wang, Xue

AU - Dammer, Eric B.

AU - Srivastava, Gyan

AU - Mukherjee, Sumit

AU - Sieberts, Solveig K.

AU - Omberg, Larsson

AU - Dang, Kristen D.

AU - Eddy, James A.

AU - Snyder, Phil

AU - Chae, Yooree

AU - Amberkar, Sandeep

AU - Wei, Wenbin

AU - Hide, Winston

AU - Preuss, Christoph

AU - Ergun, Ayla

AU - Ebert, Phillip J.

AU - Airey, David C.

AU - Mostafavi, Sara

AU - Yu, Lei

AU - Klein, Hans Ulrich

AU - Carter, Gregory W.

AU - Price, Nathan D.

PY - 2020/7/14

Y1 - 2020/7/14

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - RNA-seq

KW - aging

KW - coexpression analysis

KW - differential expression analysis

KW - meta-analysis

KW - mouse models

KW - neuroinflammation

KW - transcriptome

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DO - 10.1016/j.celrep.2020.107908

M3 - Article

C2 - 32668255

AN - SCOPUS:85087814633

SN - 2211-1247

VL - 32

JO - Cell Reports

JF - Cell Reports

IS - 2

M1 - 107908

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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