Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Song, Wilbur M., Joshita, Satoru, Zhou, Yingyue, Ulland, Tyler K., Gilfillan, Susan, Colonna, Marco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2018
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
_version_ 1783304456593473536
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
work_keys_str_mv AT songwilburm humanizedtrem2micerevealmicrogliaintrinsicandextrinsiceffectsofr47hpolymorphism
AT joshitasatoru humanizedtrem2micerevealmicrogliaintrinsicandextrinsiceffectsofr47hpolymorphism
AT zhouyingyue humanizedtrem2micerevealmicrogliaintrinsicandextrinsiceffectsofr47hpolymorphism
AT ullandtylerk humanizedtrem2micerevealmicrogliaintrinsicandextrinsiceffectsofr47hpolymorphism
AT gilfillansusan humanizedtrem2micerevealmicrogliaintrinsicandextrinsiceffectsofr47hpolymorphism
AT colonnamarco humanizedtrem2micerevealmicrogliaintrinsicandextrinsiceffectsofr47hpolymorphism