Wilbur Song1, Basavaraj Hooli2, Kristina Mullin2, Sheng Chih Jin3, Marina Cella1, Tyler K Ulland1, Yaming Wang1, Rudolph E Tanzi4, Marco Colonna5. 1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. 2. Department of Neurology, Harvard Medical School, and Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, MA, USA. 3. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. 4. Department of Neurology, Harvard Medical School, and Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, MA, USA. Electronic address: tanzi@helix.mgh.harvard.edu. 5. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: mcolonna@pathology.wustl.edu.
Abstract
INTRODUCTION: TREM2 is a lipid-sensing activating receptor on microglia known to be important for Alzheimer's disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial. METHODS: We analyzed AD risk of TREM2 variants in the NIMH AD Genetics Initiative Study and AD Sequencing Project. We compared each variant's risk and functional impact by a reporter assay. Finally, we analyzed expression of TREM2 on human monocytes. RESULTS: We provide more evidence for increased AD risk associated with several TREM2 variants, and show that these variants decreased or markedly increased binding to TREM2 ligands. We identify HDL and LDL as novel TREM2 ligands. We also show that TREM2 expression in human monocytes is minimal compared to monocyte-derived dendritic cells. DISCUSSION: Our results suggest that TREM2 signaling helps protect against AD but can cause harm in excess, supporting the idea that proper TREM2 function is important to counteract disease progression.
INTRODUCTION:TREM2 is a lipid-sensing activating receptor on microglia known to be important for Alzheimer's disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial. METHODS: We analyzed AD risk of TREM2 variants in the NIMH AD Genetics Initiative Study and AD Sequencing Project. We compared each variant's risk and functional impact by a reporter assay. Finally, we analyzed expression of TREM2 on human monocytes. RESULTS: We provide more evidence for increased AD risk associated with several TREM2 variants, and show that these variants decreased or markedly increased binding to TREM2 ligands. We identify HDL and LDL as novel TREM2 ligands. We also show that TREM2 expression in human monocytes is minimal compared to monocyte-derived dendritic cells. DISCUSSION: Our results suggest that TREM2 signaling helps protect against AD but can cause harm in excess, supporting the idea that proper TREM2 function is important to counteract disease progression.
Authors: Nan Hu; Meng-Shan Tan; Jin-Tai Yu; Lei Sun; Lin Tan; Ying-Li Wang; Teng Jiang; Lan Tan Journal: J Alzheimers Dis Date: 2014 Impact factor: 4.472
Authors: Gernot Kleinberger; Yoshinori Yamanishi; Marc Suárez-Calvet; Eva Czirr; Ebba Lohmann; Elise Cuyvers; Hanne Struyfs; Nadine Pettkus; Andrea Wenninger-Weinzierl; Fargol Mazaheri; Sabina Tahirovic; Alberto Lleó; Daniel Alcolea; Juan Fortea; Michael Willem; Sven Lammich; José L Molinuevo; Raquel Sánchez-Valle; Anna Antonell; Alfredo Ramirez; Michael T Heneka; Kristel Sleegers; Julie van der Zee; Jean-Jacques Martin; Sebastiaan Engelborghs; Asli Demirtas-Tatlidede; Henrik Zetterberg; Christine Van Broeckhoven; Hakan Gurvit; Tony Wyss-Coray; John Hardy; Marco Colonna; Christian Haass Journal: Sci Transl Med Date: 2014-07-02 Impact factor: 17.956
Authors: Thorlakur Jonsson; Hreinn Stefansson; Stacy Steinberg; Ingileif Jonsdottir; Palmi V Jonsson; Jon Snaedal; Sigurbjorn Bjornsson; Johanna Huttenlocher; Allan I Levey; James J Lah; Dan Rujescu; Harald Hampel; Ina Giegling; Ole A Andreassen; Knut Engedal; Ingun Ulstein; Srdjan Djurovic; Carla Ibrahim-Verbaas; Albert Hofman; M Arfan Ikram; Cornelia M van Duijn; Unnur Thorsteinsdottir; Augustine Kong; Kari Stefansson Journal: N Engl J Med Date: 2012-11-14 Impact factor: 91.245
Authors: W J Strittmatter; A M Saunders; D Schmechel; M Pericak-Vance; J Enghild; G S Salvesen; A D Roses Journal: Proc Natl Acad Sci U S A Date: 1993-03-01 Impact factor: 11.205
Authors: Lars Bertram; Christoph Lange; Kristina Mullin; Michele Parkinson; Monica Hsiao; Meghan F Hogan; Brit M M Schjeide; Basavaraj Hooli; Jason Divito; Iuliana Ionita; Hongyu Jiang; Nan Laird; Thomas Moscarillo; Kari L Ohlsen; Kathryn Elliott; Xin Wang; Diane Hu-Lince; Marie Ryder; Amy Murphy; Steven L Wagner; Deborah Blacker; K David Becker; Rudolph E Tanzi Journal: Am J Hum Genet Date: 2008-10-30 Impact factor: 11.025
Authors: Yaming Wang; Marina Cella; Kaitlin Mallinson; Jason D Ulrich; Katherine L Young; Michelle L Robinette; Susan Gilfillan; Gokul M Krishnan; Shwetha Sudhakar; Bernd H Zinselmeyer; David M Holtzman; John R Cirrito; Marco Colonna Journal: Cell Date: 2015-02-26 Impact factor: 41.582
Authors: Rita Guerreiro; Aleksandra Wojtas; Jose Bras; Minerva Carrasquillo; Ekaterina Rogaeva; Elisa Majounie; Carlos Cruchaga; Celeste Sassi; John S K Kauwe; Steven Younkin; Lilinaz Hazrati; John Collinge; Jennifer Pocock; Tammaryn Lashley; Julie Williams; Jean-Charles Lambert; Philippe Amouyel; Alison Goate; Rosa Rademakers; Kevin Morgan; John Powell; Peter St George-Hyslop; Andrew Singleton; John Hardy Journal: N Engl J Med Date: 2012-11-14 Impact factor: 91.245
Authors: Stefan Prokop; Kelly R Miller; Sergio R Labra; Rose M Pitkin; Kevt'her Hoxha; Sneha Narasimhan; Lakshmi Changolkar; Alyssa Rosenbloom; Virginia M-Y Lee; John Q Trojanowski Journal: Acta Neuropathol Date: 2019-07-26 Impact factor: 17.088
Authors: B Teter; T Morihara; G P Lim; T Chu; M R Jones; X Zuo; R M Paul; S A Frautschy; G M Cole Journal: Neurobiol Dis Date: 2019-04-02 Impact factor: 5.996
Authors: Qingwen Cheng; Jean Danao; Santosh Talreja; Paul Wen; Jun Yin; Ning Sun; Chi-Ming Li; Danny Chui; David Tran; Samir Koirala; Hang Chen; Ian N Foltz; Songli Wang; Shilpa Sambashivan Journal: J Biol Chem Date: 2018-03-29 Impact factor: 5.157