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Reactive or transgenic increase in microglial TYROBP reveals a TREM2‐independent TYROBP–APOE link in wild‐type and Alzheimer's‐related mice
INTRODUCTION: Microglial TYROBP (DAP12) is a network hub and driver in sporadic late‐onset Alzheimer's disease (AD). TYROBP is a cytoplasmic adaptor for TREM2 and other receptors, but little is known about its roles and actions in AD. Herein, we demonstrate that endogenous Tyrobp transcription...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938663/ https://www.ncbi.nlm.nih.gov/pubmed/33314529 http://dx.doi.org/10.1002/alz.12256 |
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author | Audrain, Mickael Haure‐Mirande, Jean‐Vianney Mleczko, Justyna Wang, Minghui Griffin, Jennifer K. St George‐Hyslop, Peter H. Fraser, Paul Zhang, Bin Gandy, Sam Ehrlich, Michelle E. |
author_facet | Audrain, Mickael Haure‐Mirande, Jean‐Vianney Mleczko, Justyna Wang, Minghui Griffin, Jennifer K. St George‐Hyslop, Peter H. Fraser, Paul Zhang, Bin Gandy, Sam Ehrlich, Michelle E. |
author_sort | Audrain, Mickael |
collection | PubMed |
description | INTRODUCTION: Microglial TYROBP (DAP12) is a network hub and driver in sporadic late‐onset Alzheimer's disease (AD). TYROBP is a cytoplasmic adaptor for TREM2 and other receptors, but little is known about its roles and actions in AD. Herein, we demonstrate that endogenous Tyrobp transcription is specifically increased in recruited microglia. METHODS: Using a novel transgenic mouse overexpressing TYROBP in microglia, we observed a decrease of the amyloid burden and an increase of TAU phosphorylation stoichiometry when crossed with APP/PSEN1 or MAPT(P301S) mice, respectively. Characterization of these mice revealed Tyrobp‐related modulation of apolipoprotein E (Apoe) transcription. We also showed that Tyrobp and Apoe mRNAs were increased in Trem2‐null microglia recruited around either amyloid beta deposits or a cortical stab injury. Conversely, microglial Apoe transcription was dramatically diminished when Tyrobp was absent. CONCLUSIONS: Our results provide evidence that TYROBP‐APOE signaling does not require TREM2 and could be an initiating step in establishment of the disease‐associated microglia (DAM) phenotype. |
format | Online Article Text |
id | pubmed-7938663 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-79386632021-03-24 Reactive or transgenic increase in microglial TYROBP reveals a TREM2‐independent TYROBP–APOE link in wild‐type and Alzheimer's‐related mice Audrain, Mickael Haure‐Mirande, Jean‐Vianney Mleczko, Justyna Wang, Minghui Griffin, Jennifer K. St George‐Hyslop, Peter H. Fraser, Paul Zhang, Bin Gandy, Sam Ehrlich, Michelle E. Alzheimers Dement Featured Article INTRODUCTION: Microglial TYROBP (DAP12) is a network hub and driver in sporadic late‐onset Alzheimer's disease (AD). TYROBP is a cytoplasmic adaptor for TREM2 and other receptors, but little is known about its roles and actions in AD. Herein, we demonstrate that endogenous Tyrobp transcription is specifically increased in recruited microglia. METHODS: Using a novel transgenic mouse overexpressing TYROBP in microglia, we observed a decrease of the amyloid burden and an increase of TAU phosphorylation stoichiometry when crossed with APP/PSEN1 or MAPT(P301S) mice, respectively. Characterization of these mice revealed Tyrobp‐related modulation of apolipoprotein E (Apoe) transcription. We also showed that Tyrobp and Apoe mRNAs were increased in Trem2‐null microglia recruited around either amyloid beta deposits or a cortical stab injury. Conversely, microglial Apoe transcription was dramatically diminished when Tyrobp was absent. CONCLUSIONS: Our results provide evidence that TYROBP‐APOE signaling does not require TREM2 and could be an initiating step in establishment of the disease‐associated microglia (DAM) phenotype. John Wiley and Sons Inc. 2020-12-12 2021-02 /pmc/articles/PMC7938663/ /pubmed/33314529 http://dx.doi.org/10.1002/alz.12256 Text en © 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Featured Article Audrain, Mickael Haure‐Mirande, Jean‐Vianney Mleczko, Justyna Wang, Minghui Griffin, Jennifer K. St George‐Hyslop, Peter H. Fraser, Paul Zhang, Bin Gandy, Sam Ehrlich, Michelle E. Reactive or transgenic increase in microglial TYROBP reveals a TREM2‐independent TYROBP–APOE link in wild‐type and Alzheimer's‐related mice |
title | Reactive or transgenic increase in microglial TYROBP reveals a TREM2‐independent TYROBP–APOE link in wild‐type and Alzheimer's‐related mice |
title_full | Reactive or transgenic increase in microglial TYROBP reveals a TREM2‐independent TYROBP–APOE link in wild‐type and Alzheimer's‐related mice |
title_fullStr | Reactive or transgenic increase in microglial TYROBP reveals a TREM2‐independent TYROBP–APOE link in wild‐type and Alzheimer's‐related mice |
title_full_unstemmed | Reactive or transgenic increase in microglial TYROBP reveals a TREM2‐independent TYROBP–APOE link in wild‐type and Alzheimer's‐related mice |
title_short | Reactive or transgenic increase in microglial TYROBP reveals a TREM2‐independent TYROBP–APOE link in wild‐type and Alzheimer's‐related mice |
title_sort | reactive or transgenic increase in microglial tyrobp reveals a trem2‐independent tyrobp–apoe link in wild‐type and alzheimer's‐related mice |
topic | Featured Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938663/ https://www.ncbi.nlm.nih.gov/pubmed/33314529 http://dx.doi.org/10.1002/alz.12256 |
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