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TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor that recognizes changes in the lipid microenvironment, which may occur during amyloid β (Aβ) accumulation and neuronal degeneration in Alzheimer’s disease (AD). Rare TREM2 variants that affect TREM2 function lead to an...

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Autores principales: Wang, Yaming, Ulland, Tyler K., Ulrich, Jason D., Song, Wilbur, Tzaferis, John A., Hole, Justin T., Yuan, Peng, Mahan, Thomas E., Shi, Yang, Gilfillan, Susan, Cella, Marina, Grutzendler, Jaime, DeMattos, Ronald B., Cirrito, John R., Holtzman, David M., Colonna, Marco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854736/
https://www.ncbi.nlm.nih.gov/pubmed/27091843
http://dx.doi.org/10.1084/jem.20151948
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author Wang, Yaming
Ulland, Tyler K.
Ulrich, Jason D.
Song, Wilbur
Tzaferis, John A.
Hole, Justin T.
Yuan, Peng
Mahan, Thomas E.
Shi, Yang
Gilfillan, Susan
Cella, Marina
Grutzendler, Jaime
DeMattos, Ronald B.
Cirrito, John R.
Holtzman, David M.
Colonna, Marco
author_facet Wang, Yaming
Ulland, Tyler K.
Ulrich, Jason D.
Song, Wilbur
Tzaferis, John A.
Hole, Justin T.
Yuan, Peng
Mahan, Thomas E.
Shi, Yang
Gilfillan, Susan
Cella, Marina
Grutzendler, Jaime
DeMattos, Ronald B.
Cirrito, John R.
Holtzman, David M.
Colonna, Marco
author_sort Wang, Yaming
collection PubMed
description Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor that recognizes changes in the lipid microenvironment, which may occur during amyloid β (Aβ) accumulation and neuronal degeneration in Alzheimer’s disease (AD). Rare TREM2 variants that affect TREM2 function lead to an increased risk of developing AD. In murine models of AD, TREM2 deficiency prevents microglial clustering around Aβ deposits. However, the origin of myeloid cells surrounding amyloid and the impact of TREM2 on Aβ accumulation are a matter of debate. Using parabiosis, we found that amyloid-associated myeloid cells derive from brain-resident microglia rather than from recruitment of peripheral blood monocytes. To determine the impact of TREM2 deficiency on Aβ accumulation, we examined Aβ plaques in the 5XFAD model of AD at the onset of Aβ-related pathology. At this early time point, Aβ accumulation was similar in TREM2-deficient and -sufficient 5XFAD mice. However, in the absence of TREM2, Aβ plaques were not fully enclosed by microglia; they were more diffuse, less dense, and were associated with significantly greater neuritic damage. Thus, TREM2 protects from AD by enabling microglia to surround and alter Aβ plaque structure, thereby limiting neuritic damage.
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spelling pubmed-48547362016-11-02 TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques Wang, Yaming Ulland, Tyler K. Ulrich, Jason D. Song, Wilbur Tzaferis, John A. Hole, Justin T. Yuan, Peng Mahan, Thomas E. Shi, Yang Gilfillan, Susan Cella, Marina Grutzendler, Jaime DeMattos, Ronald B. Cirrito, John R. Holtzman, David M. Colonna, Marco J Exp Med Research Articles Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor that recognizes changes in the lipid microenvironment, which may occur during amyloid β (Aβ) accumulation and neuronal degeneration in Alzheimer’s disease (AD). Rare TREM2 variants that affect TREM2 function lead to an increased risk of developing AD. In murine models of AD, TREM2 deficiency prevents microglial clustering around Aβ deposits. However, the origin of myeloid cells surrounding amyloid and the impact of TREM2 on Aβ accumulation are a matter of debate. Using parabiosis, we found that amyloid-associated myeloid cells derive from brain-resident microglia rather than from recruitment of peripheral blood monocytes. To determine the impact of TREM2 deficiency on Aβ accumulation, we examined Aβ plaques in the 5XFAD model of AD at the onset of Aβ-related pathology. At this early time point, Aβ accumulation was similar in TREM2-deficient and -sufficient 5XFAD mice. However, in the absence of TREM2, Aβ plaques were not fully enclosed by microglia; they were more diffuse, less dense, and were associated with significantly greater neuritic damage. Thus, TREM2 protects from AD by enabling microglia to surround and alter Aβ plaque structure, thereby limiting neuritic damage. The Rockefeller University Press 2016-05-02 /pmc/articles/PMC4854736/ /pubmed/27091843 http://dx.doi.org/10.1084/jem.20151948 Text en © 2016 Wang et al. 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 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Wang, Yaming
Ulland, Tyler K.
Ulrich, Jason D.
Song, Wilbur
Tzaferis, John A.
Hole, Justin T.
Yuan, Peng
Mahan, Thomas E.
Shi, Yang
Gilfillan, Susan
Cella, Marina
Grutzendler, Jaime
DeMattos, Ronald B.
Cirrito, John R.
Holtzman, David M.
Colonna, Marco
TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
title TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
title_full TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
title_fullStr TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
title_full_unstemmed TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
title_short TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
title_sort trem2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854736/
https://www.ncbi.nlm.nih.gov/pubmed/27091843
http://dx.doi.org/10.1084/jem.20151948
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