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Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism
Alzheimer’s disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-β plaques ch...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839761/ https://www.ncbi.nlm.nih.gov/pubmed/29321225 http://dx.doi.org/10.1084/jem.20171529 |
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author | Song, Wilbur M. Joshita, Satoru Zhou, Yingyue Ulland, Tyler K. Gilfillan, Susan Colonna, Marco |
author_facet | Song, Wilbur M. Joshita, Satoru Zhou, Yingyue Ulland, Tyler K. Gilfillan, Susan Colonna, Marco |
author_sort | Song, Wilbur M. |
collection | PubMed |
description | Alzheimer’s disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-β plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown. We generated transgenic mice expressing human CV or R47H TREM2 and lacking endogenous TREM2 in the 5XFAD AD model. Only the CV transgene restored amyloid-β–induced microgliosis and microglial activation, indicating that R47H impairs TREM2 function in vivo. Remarkably, soluble TREM2 was found on neurons and plaques in CV- but not R47H-expressing 5XFAD brains, although in vitro CV and R47H were shed similarly via Adam17 proteolytic activity. These results demonstrate that TREM2 interacts with neurons and plaques duing amyloid-β accumulation and R47H impairs this interaction. |
format | Online Article Text |
id | pubmed-5839761 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-58397612018-09-05 Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism Song, Wilbur M. Joshita, Satoru Zhou, Yingyue Ulland, Tyler K. Gilfillan, Susan Colonna, Marco J Exp Med Research Articles Alzheimer’s disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-β plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown. We generated transgenic mice expressing human CV or R47H TREM2 and lacking endogenous TREM2 in the 5XFAD AD model. Only the CV transgene restored amyloid-β–induced microgliosis and microglial activation, indicating that R47H impairs TREM2 function in vivo. Remarkably, soluble TREM2 was found on neurons and plaques in CV- but not R47H-expressing 5XFAD brains, although in vitro CV and R47H were shed similarly via Adam17 proteolytic activity. These results demonstrate that TREM2 interacts with neurons and plaques duing amyloid-β accumulation and R47H impairs this interaction. The Rockefeller University Press 2018-03-05 /pmc/articles/PMC5839761/ /pubmed/29321225 http://dx.doi.org/10.1084/jem.20171529 Text en © 2018 Song et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Song, Wilbur M. Joshita, Satoru Zhou, Yingyue Ulland, Tyler K. Gilfillan, Susan Colonna, Marco Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism |
title | Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism |
title_full | Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism |
title_fullStr | Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism |
title_full_unstemmed | Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism |
title_short | Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism |
title_sort | humanized trem2 mice reveal microglia-intrinsic and -extrinsic effects of r47h polymorphism |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839761/ https://www.ncbi.nlm.nih.gov/pubmed/29321225 http://dx.doi.org/10.1084/jem.20171529 |
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