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
TLDR
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.Abstract:
Our understanding of Alzheimer's disease (AD) pathophysiology remains incomplete. Here we used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study thus far on AD. A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with AD pathology and cognitive impairment. This module was enriched in AD genetic risk factors and in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were elevated in cerebrospinal fluid in early stages of the disease. In this study of >2,000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brains that may serve as therapeutic targets and fluid biomarkers for the disease.read more
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Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing
Stephen C. Cunnane,Eugenia Trushina,Cecilie Morland,Alessandro Prigione,Gemma Casadesus,Zane B. Andrews,M. Flint Beal,Linda H. Bergersen,Roberta Diaz Brinton,Suzanne M. de la Monte,Anne Eckert,Jenni Harvey,Ross Jeggo,Jack H. Jhamandas,Oliver Kann,Clotilde Mannoury la Cour,William Martin,Gilles Mithieux,Paula I. Moreira,Michael P. Murphy,Klaus-Armin Nave,Tal Nuriel,Stéphane H. R. Oliet,Stéphane H. R. Oliet,Frédéric Saudou,Frédéric Saudou,Mark P. Mattson,Russell H. Swerdlow,Millan Mark +28 more
TL;DR: The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.
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
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.
Journal ArticleDOI
Proteome profiling in cerebrospinal fluid reveals novel biomarkers of Alzheimer's disease
Jakob M. Bader,Philipp E. Geyer,Philipp E. Geyer,Johannes Müller,Maximilian T. Strauss,Manja Koch,Frank Leypoldt,Peter Koertvelyessy,Peter Koertvelyessy,Daniel Bittner,Carola G. Schipke,Enise I. Incesoy,Oliver Peters,Oliver Peters,Nikolaus Deigendesch,Mikael Simons,Majken K. Jensen,Majken K. Jensen,Henrik Zetterberg,Matthias Mann,Matthias Mann +20 more
TL;DR: A highly reproducible mass spectrometry (MS)‐based proteomics workflow for the in‐depth analysis of CSF from minimal sample amounts is presented and a consistent glycolytic signature across cohorts and a recent study suggests clinical utility of this proteomic signature.
Journal ArticleDOI
Large-scale deep multi-layer analysis of Alzheimer’s disease brain reveals strong proteomic disease-related changes not observed at the RNA level
TL;DR: This article analyzed the proteomes of more than 1,000 brain tissues to reveal new AD-related protein co-expression modules that were highly preserved across cohorts and brain regions, highlighting the proteopathic nature of AD.
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