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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.

SUBMITTER: Wan YW

PROVIDER: S-EPMC7428328 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Wan Ying-Wooi YW Al-Ouran Rami R Mangleburg Carl G CG Perumal Thanneer M TM Lee Tom V TV Allison Katherine K Swarup Vivek V Funk Cory C CC Gaiteri Chris C Allen Mariet M Wang Minghui M Neuner Sarah M SM Kaczorowski Catherine C CC Philip Vivek M VM Howell Gareth R GR Martini-Stoica Heidi H Zheng Hui H Mei Hongkang H Zhong Xiaoyan X Kim Jungwoo Wren JW Dawson Valina L VL Dawson Ted M TM Pao Ping-Chieh PC Tsai Li-Huei LH Haure-Mirande Jean-Vianney JV Ehrlich Michelle E ME Chakrabarty Paramita P Levites Yona Y Wang Xue X Dammer Eric B EB Srivastava Gyan G Mukherjee Sumit S Sieberts Solveig K SK Omberg Larsson L Dang Kristen D KD Eddy James A JA Snyder Phil P Chae Yooree Y Amberkar Sandeep S Wei Wenbin W Hide Winston W Preuss Christoph C Ergun Ayla A Ebert Phillip J PJ Airey David C DC Mostafavi Sara S Yu Lei L Klein Hans-Ulrich HU Carter Gregory W GW Collier David A DA Golde Todd E TE Levey Allan I AI Bennett David A DA Estrada Karol K Townsend T Matthew TM Zhang Bin B Schadt Eric E De Jager Philip L PL Price Nathan D ND Ertekin-Taner Nilüfer N Liu Zhandong Z Shulman Joshua M JM Mangravite Lara M LM Logsdon Benjamin A BA

Cell reports 20200701 2

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 patholo ...[more]

PMID: 32668255

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Project description:PurposeThe triggering receptor expressed on myeloid cells 2 (TREM2) is expressed by brain microglia. Microglial activation, as observed in Alzheimer's disease (AD) as well as in transgenic mice expressing human amyloid-beta, appears to increase soluble TREM2 (sTREM2) levels in CSF and brain. In this study, we used two different transgenic mouse models of AD pathology and investigated the potential of TREM2 to serve as an in vivo biomarker for microglial activation in AD.ProceduresWe designed and generated a bispecific antibody based on the TREM2-specific monoclonal antibody mAb1729, fused to a single-chain variable fragment of the transferrin receptor binding antibody 8D3. The 8D3-moiety enabled transcytosis of the whole bispecific antibody across the blood-brain barrier. The bispecific antibody was radiolabeled with I-125 (ex vivo) or I-124 (PET) and administered to transgenic AD and wild-type (WT) control mice. Radioligand retention in the brain of transgenic animals was compared to WT mice by isolation of brain tissue at 24 h or 72 h, or with in vivo PET at 24 h, 48 h, and 72 h. Intrabrain distribution of radiolabeled mAb1729-scFv8D3CL was further studied by autoradiography, while ELISA was used to determine TREM2 brain concentrations.ResultsTransgenic animals displayed higher total exposure, calculated as the AUC based on SUV determined at 24h, 48h, and 72h post injection, of PET radioligand [124I]mAb1729-scFv8D3CL than WT mice. However, differences were not evident in single time point PET images or SUVs. Ex vivo autoradiography confirmed higher radioligand concentrations in cortex and thalamus in transgenic mice compared to WT, and TREM2 levels in brain homogenates were considerably higher in transgenic mice compared to WT.ConclusionAntibody-based radioligands, engineered to enter the brain, may serve as PET radioligands to follow changes of TREM2 in vivo, but antibody formats with faster systemic clearance to increase the specific signal in relation to that from blood in combination with antibodies showing higher affinity for TREM2 must be developed to further progress this technique for in vivo use.

Dataset Information

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

Publications

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

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