Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease
Yingyue Zhou,Wilbur M. Song,Prabhakar S. Andhey,Amanda Swain,Tyler Levy,Kelly R. Miller,Pietro Luigi Poliani,Manuela Cominelli,Shikha Grover,Susan Gilfillan,Marina Cella,Tyler K. Ulland,Konstantin Zaitsev,Konstantin Zaitsev,Akinori Miyashita,Takeshi Ikeuchi,Makoto Sainouchi,Akiyoshi Kakita,David A. Bennett,Julie A. Schneider,Michael R. Nichols,Sean A. Beausoleil,Jason D. Ulrich,David M. Holtzman,Maxim N. Artyomov,Marco Colonna +25 more
TLDR
Single-nucleus RNA sequencing in a mouse model of Aβ accumulation and postmortem brain tissue from people with Alzheimer’s disease reveals substantial species-specific differences in transcriptional signatures, but both point to the contribution of glia and the importance of TREM2.Abstract:
Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.read more
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Reactive astrocyte nomenclature, definitions, and future directions
Carole Escartin,Elena Galea,Andras Lakatos,James P. O'Callaghan,Gabor C. Petzold,Gabor C. Petzold,Alberto Serrano-Pozo,Christian Steinhäuser,Andrea Volterra,Giorgio Carmignoto,Giorgio Carmignoto,Amit Agarwal,Nicola J. Allen,Alfonso Araque,Luis Barbeito,Ari Barzilai,Dwight E. Bergles,Gilles Bonvento,Arthur M. Butt,Wei Ting Chen,Martine Cohen-Salmon,Colm Cunningham,Benjamin Deneen,Bart De Strooper,Bart De Strooper,Blanca Diaz-Castro,Cinthia Farina,Marc R. Freeman,Vittorio Gallo,James E. Goldman,Steven A. Goldman,Steven A. Goldman,Magdalena Götz,Antonia Gutierrez,Philip G. Haydon,Dieter Henrik Heiland,Elly M. Hol,Matthew Holt,Masamitsu Iino,Ksenia V. Kastanenka,Helmut Kettenmann,Baljit S. Khakh,Schuichi Koizumi,C. Justin Lee,Shane A. Liddelow,Brian A. MacVicar,Pierre J. Magistretti,Pierre J. Magistretti,Albee Messing,Anusha Mishra,Anna V. Molofsky,Keith K. Murai,Christopher M. Norris,Seiji Okada,Stéphane H. R. Oliet,João Filipe Oliveira,João Filipe Oliveira,Aude Panatier,Vladimir Parpura,Marcela Pekna,Milos Pekny,Luc Pellerin,Gertrudis Perea,Beatriz G. Pérez-Nievas,Frank W. Pfrieger,Kira E. Poskanzer,Francisco J. Quintana,Richard M. Ransohoff,Miriam Riquelme-Perez,Stefanie Robel,Christine R. Rose,Jeffrey D. Rothstein,Nathalie Rouach,David H. Rowitch,Alexey Semyanov,Alexey Semyanov,Swetlana Sirko,Harald Sontheimer,Raymond A. Swanson,Javier Vitorica,Ina B. Wanner,Levi B. Wood,Jia Qian Wu,Binhai Zheng,Eduardo R. Zimmer,Robert Zorec,Michael V. Sofroniew,Alexei Verkhratsky,Alexei Verkhratsky +88 more
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Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer's Disease.
Wei Ting Chen,Wei Ting Chen,Ashley Lu,Ashley Lu,Katleen Craessaerts,Katleen Craessaerts,Benjamin Pavie,Carlo Sala Frigerio,Carlo Sala Frigerio,Carlo Sala Frigerio,Nikky Corthout,Xiaoyan Qian,Jana Lalakova,Malte Kühnemund,Iryna Voytyuk,Iryna Voytyuk,Leen Wolfs,Leen Wolfs,Renzo Mancuso,Renzo Mancuso,Evgenia Salta,Evgenia Salta,Sriram Balusu,Sriram Balusu,An Snellinx,An Snellinx,Sebastian Munck,Aleksandra Jurek,José Fernández Navarro,Takaomi C. Saido,Inge Huitinga,Inge Huitinga,Joakim Lundeberg,Mark Fiers,Mark Fiers,Mark Fiers,Bart De Strooper,Bart De Strooper,Bart De Strooper +38 more
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APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches
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Dysregulation of brain and choroid plexus cell types in severe COVID-19.
Andrew C. Yang,Fabian Kern,Patricia Moran Losada,Maayan R. Agam,Christina A. Maat,Georges Pierre Schmartz,Tobias Fehlmann,Julian A. Stein,Nicholas Schaum,Davis P. Lee,Kruti Calcuttawala,Ryan T. Vest,Daniela Berdnik,Nannan Lu,Oliver Hahn,David Gate,M. Windy McNerney,Divya Channappa,Inma Cobos,Nicole Ludwig,Walter J. Schulz-Schaeffer,Andreas Keller,Andreas Keller,Tony Wyss-Coray +23 more
TL;DR: In this article, single-nucleus transcriptomes of frontal cortex and choroid plexus samples from patients with COVID-19 reveal pathological cell states that are similar to those associated with human neurodegenerative diseases and chronic brain disorders.
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The Amyloid-β Pathway in Alzheimer's Disease.
Harald Hampel,John Hardy,Kaj Blennow,Kaj Blennow,Christopher Chen,George Perry,Seung Hyun Kim,Victor L. Villemagne,Victor L. Villemagne,Paul S. Aisen,Michele Vendruscolo,Takeshi Iwatsubo,Colin L. Masters,Min Cho,Lars Lannfelt,Jeffrey L. Cummings,Andrea Vergallo +16 more
TL;DR: In this paper, the authors systematically review and update the vast state-of-the-art literature of amyloid-β (Aβ) science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics.
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