Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease
Erik C. B. Johnson,Eric B. Dammer,Duc M. Duong,Luming Yin,Madhav Thambisetty,Juan C. Troncoso,James J. Lah,Allan I. Levey,Nicholas T. Seyfried +8 more
TLDR
A new proteomic systems-level analysis of AD brain based on 6,533 proteins measured across AD, AsymAD, and controls using an analysis pipeline consisting of isobaric tandem mass tag (TMT) mass spectrometry and offline prefractionation is reported.Abstract:
The complicated cellular and biochemical changes that occur in brain during Alzheimer’s disease are poorly understood. In a previous study we used an unbiased label-free quantitative mass spectrometry-based proteomic approach to analyze these changes at a systems level in post-mortem cortical tissue from patients with Alzheimer’s disease (AD), asymptomatic Alzheimer’s disease (AsymAD), and controls. We found modules of co-expressed proteins that correlated with AD phenotypes, some of which were enriched in proteins identified as risk factors for AD by genetic studies. The amount of information that can be obtained from such systems-level proteomic analyses is critically dependent upon the number of proteins that can be quantified across a cohort. We report here a new proteomic systems-level analysis of AD brain based on 6,533 proteins measured across AD, AsymAD, and controls using an analysis pipeline consisting of isobaric tandem mass tag (TMT) mass spectrometry and offline prefractionation. Our new TMT pipeline allowed us to more than double the depth of brain proteome coverage. This increased depth of coverage greatly expanded the brain protein network to reveal new protein modules that correlated with disease and were unrelated to those identified in our previous network. Differential protein abundance analysis identified 350 proteins that had altered levels between AsymAD and AD not caused by changes in specific cell type abundance, potentially reflecting biochemical changes that are associated with cognitive decline in AD. RNA binding proteins emerged as a class of proteins altered between AsymAD and AD, and were enriched in network modules that correlated with AD pathology. We developed a proteogenomic approach to investigate RNA splicing events that may be altered by RNA binding protein changes in AD. The increased proteome depth afforded by our TMT pipeline allowed us to identify and quantify a large number of alternatively spliced protein isoforms in brain, including AD risk factors such as BIN1, PICALM, PTK2B, and FERMT2. Many of the new AD protein network modules were enriched in alternatively spliced proteins and correlated with molecular markers of AD pathology and cognition. Further analysis of the AD brain proteome will continue to yield new insights into the biological basis of AD.read more
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Journal ArticleDOI
Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation
Erik C. B. Johnson,Eric B. Dammer,Duc M. Duong,Lingyan Ping,Maotian Zhou,Luming Yin,Lenora Higginbotham,Andrew Guajardo,Bartholomew White,Juan C. Troncoso,Madhav Thambisetty,Thomas J. Montine,Edward B. Lee,John Q. Trojanowski,Thomas G. Beach,Eric M. Reiman,Vahram Haroutunian,Vahram Haroutunian,Minghui Wang,Eric E. Schadt,Bin Zhang,Dennis W. Dickson,Nilufer Ertekin-Taner,Todd E. Golde,Vladislav A. Petyuk,Philip L. De Jager,David A. Bennett,Thomas S. Wingo,Srikant Rangaraju,Ihab Hajjar,Joshua M. Shulman,James J. Lah,Allan I. Levey,Nicholas T. Seyfried +33 more
TL;DR: Large-scale, comprehensive proteomic profiling of Alzheimer’s disease brain and cerebrospinal fluid reveals disease-associated protein coexpression modules and highlights the importance of glia and energy metabolism in disease pathogenesis.
Journal ArticleDOI
The multiplex model of the genetics of Alzheimer’s disease
TL;DR: The multiplex model reflects the combination of some, or all, of these model components (genetic and environmental), in a tissue-specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell and synaptic loss observed in AD.
Journal ArticleDOI
Meta-Analysis of the Alzheimer's Disease Human Brain Transcriptome and Functional Dissection in Mouse Models.
Ying-Wooi Wan,Ying-Wooi Wan,Rami Al-Ouran,Rami Al-Ouran,Carl Grant Mangleburg,Carl Grant Mangleburg,Thanneer M. Perumal,Tom V. Lee,Tom V. Lee,Katherine Allison,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,Ping-Chieh Pao,Li-Huei Tsai,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,Sandeep Amberkar,Wenbin Wei,Wenbin Wei,Winston Hide,Winston Hide,Christoph Preuss,Ayla Ergun,Phillip J. Ebert,David C. Airey,Sara Mostafavi,Lei Yu,Hans-Ulrich Klein,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 E. Schadt,Philip L. De Jager,Philip L. De Jager,Nathan D. Price,Nilufer Ertekin-Taner,Zhandong Liu,Zhandong Liu,Joshua M. Shulman,Lara M. Mangravite,Benjamin A. Logsdon +76 more
TL;DR: 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, is presented, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.
Journal ArticleDOI
APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids
Jing Zhao,Yuan Fu,Yu Yamazaki,Yingxue Ren,Mary D. Davis,Chia Chen Liu,Wenyan Lu,Xue Wang,Kai Chen,Yesesri Cherukuri,Lin Jia,Yuka A. Martens,Lucy Job,Francis Shue,Thanh Thanh L. Nguyen,Steven G. Younkin,Neill R. Graff-Radford,Zbigniew K. Wszolek,David A. Brafman,Yan W. Asmann,Nilufer Ertekin-Taner,Takahisa Kanekiyo,Guojun Bu +22 more
TL;DR: Together, these studies develop cerebral organoid models using induced pluripotent stem cells with APOE ε3/ε3 or ε4/ε4 genotypes and suggest APOE4-related degenerative pathways contributing to AD pathogenesis are suggested.
Journal ArticleDOI
Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease
Lenora Higginbotham,Lingyan Ping,Eric B. Dammer,Duc M. Duong,Maotian Zhou,Marla Gearing,Cheyenne Hurst,Jonathan D. Glass,Stewart A. Factor,Erik C. B. Johnson,Ihab Hajjar,James J. Lah,Allan I. Levey,Nicholas T. Seyfried +13 more
TL;DR: Results are a promising step toward a network-based biomarker tool for AD clinical applications and identify cerebrospinal fluid biomarkers representing a wide spectrum of AD pathophysiology.
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