@article{2cb8243bae914a46a2ec620539b32682,
title = "Impact of TREM2R47Hvariant on tau pathology-induced gliosis and neurodegeneration",
abstract = "Alzheimer's disease (AD) is characterized by plaques containing amyloid-β (Aβ) and neurofibrillary tangles composed of aggregated, hyperphosphorylated tau. Beyond tau and Aβ, evidence suggests that microglia play an important role in AD pathogenesis. Rare variants in the microglia-expressed triggering receptor expressed on myeloid cells 2 (TREM2) gene increase AD risk 2- to 4-fold. It is likely that these TREM2 variants increase AD risk by decreasing the response of microglia to Aβ and its local toxicity. However, neocortical Aβ pathology occurs many years before neocortical tau pathology in AD. Thus, it will be important to understand the role of TREM2 in the context of tauopathy. We investigated the impact of the ADassociated TREM2 variant (R47H) on tau-mediated neuropathology in the PS19 mouse model of tauopathy. We assessed PS19 mice expressing human TREM2CV (common variant) or human TREM2R47H. PS19-TREM2R47H mice had significantly attenuated brain atrophy and synapse loss versus PS19-TREM2CV mice. Gene expression analyses and CD68 immunostaining revealed attenuated microglial reactivity in PS19-TREM2R47H versus PS19-TREM2CV mice. There was also a decrease in phagocytosis of postsynaptic elements by microglia expressing TREM2R47H in the PS19 mice and in human AD brains. These findings suggest that impaired TREM2 signaling reduces microglia-mediated neurodegeneration in the setting of tauopathy.",
author = "Maud Gratuze and Leyns, {Cheryl E.G.} and Sauerbeck, {Andrew D.} and St-Pierre, {Marie Kim} and Monica Xiong and Nayeon Kim and Serrano, {Javier Remolina} and Tremblay, {Marie {\`E}ve} and Kummer, {Terrance T.} and Marco Colonna and Ulrich, {Jason D.} and Holtzman, {David M.}",
note = "Funding Information: This study was supported by the McDonnell Center for Cellular and Molecular Neurobiology (to MG), NIH grant AG047644, the JPB Foundation, the Charles and Helen Schwab Foundation (to DMH), and the Edward N. and Della L. Thome Memorial Foundation, Bank of America, N.A., Trustee (to DMH). Scanning of immunohistochemistry was performed on the NanoZoomer digital pathology system courtesy of the Hope Center Alafi Neuroimaging Laboratory. Confocal data were generated on a Zeiss LSM 880 Airyscan Confocal Microscope, which was purchased with support from the Office of Research Infrastructure Programs (ORIP), a part of the NIH Office of the Director under grant OD021629, and in part with support from the Washington University Center for Cellular Imaging (WUCCI) supported by Washington University School of Medicine, The Children{\textquoteright}s Discovery Institute of Washington University and St. Louis Children{\textquoteright}s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813), and the Foundation for Barnes-Jewish Hospital (3770 and 4642). We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by NCI Cancer Center Support grant P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA grant UL1 TR000448 from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of the NCRR or the NIH. The authors specifically thank David Blum for his helpful advice during the study. Funding Information: This study was supported by the McDonnell Center for Cellular and Molecular Neurobiology (to MG), NIH grant AG047644, the JPB Foundation, the Charles and Helen Schwab Foundation (to DMH), and the Edward N. and Della L. Thome Memorial Foundation, Bank of America, N.A., Trustee (to DMH). Scanning of immunohistochemistry was performed on the NanoZoomer digital pathology system courtesy of the Hope Center Alafi Neuroimaging Laboratory. Confocal data were generated on a Zeiss LSM 880 Airyscan Confocal Microscope, which was purchased with support from the Office of Research Infrastructure Programs (ORIP), a part of the NIH Office of the Director under grant OD021629, and in part with support from the Washington University Center for Cellular Imaging (WUCCI) supported by Washington University School of Medicine, The Children's Discovery Institute of Washington University and St. Louis Children's Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813), and the Foundation for Barnes-Jewish Hospital (3770 and 4642). We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by NCI Cancer Center Support grant P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA grant UL1 TR000448 from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of the NCRR or the NIH. The authors specifically thank David Blum for his helpful advice during the study. Funding Information: Conflict of interest: DMH and JDU are listed as inventors on a provisional patent from Washington University on TREM2 antibodies. DMH and CEGL are listed as inventors on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. CEGL is currently an employee at Merck. MC receives research funding from Alector, Amgen, and Ono. DMH cofounded and is on the scientific advisory board of C2N Diagnostics. C2N Diagnostics has licensed certain anti-tau antibodies to AbbVie for therapeutic development. DMH is on the scientific advisory board of Denali and consults for Genentech and Idorsia. Copyright: {\textcopyright} 2020, American Society for Clinical Investigation. Submitted: March 16, 2020; Accepted: June 10, 2020; Published: August 17, 2020. Reference information: J Clin Invest. 2020;130(9):4954–4968. https://doi.org/10.1172/JCI138179. Publisher Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",
year = "2020",
month = sep,
day = "1",
doi = "10.1172/JCI138179",
language = "English",
volume = "130",
pages = "4954--4968",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
number = "9",
}