Cargando…

TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’s disease mice

Triggering receptor expressed on myeloid cells 2 (TREM2) has been shown with a neuroprotective function against inflammation and neuronal injury in Alzheimer’s disease (AD). However, the TREM2 induced anti-inflammatory mechanism is still not well known. In this study it has been demonstrated that th...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Yaping, Lin, Yan, Wang, Linhan, Zhan, Hongrui, Luo, Xiaoting, Zeng, Yanyan, Wu, Wen, Zhang, Xingmei, Wang, Fang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655179/
https://www.ncbi.nlm.nih.gov/pubmed/33065553
http://dx.doi.org/10.18632/aging.104104
_version_ 1783608187895676928
author Wang, Yaping
Lin, Yan
Wang, Linhan
Zhan, Hongrui
Luo, Xiaoting
Zeng, Yanyan
Wu, Wen
Zhang, Xingmei
Wang, Fang
author_facet Wang, Yaping
Lin, Yan
Wang, Linhan
Zhan, Hongrui
Luo, Xiaoting
Zeng, Yanyan
Wu, Wen
Zhang, Xingmei
Wang, Fang
author_sort Wang, Yaping
collection PubMed
description Triggering receptor expressed on myeloid cells 2 (TREM2) has been shown with a neuroprotective function against inflammation and neuronal injury in Alzheimer’s disease (AD). However, the TREM2 induced anti-inflammatory mechanism is still not well known. In this study it has been demonstrated that the expression of TREM2 was upregulated in hippocampus of 5xFAD mice, whereas TREM2 knock-out mediated by AAV significantly increased the levels of pro-inflammatory cytokines and aggravated cognitive defect. Additionally, FoxO3a, a downstream member of the PI3K/AKT pathway, could be activated by TREM2 defect via the PI3K/AKT signaling in 5xFAD mice. That suggests TREM2-induced protection is associated with the PI3K-FoxO3a axis. On the contrary, overexpression of TREM2 alleviated the LPS-induced inflammatory response and induced M2 phenotype microglia in vitro. This phenomenon can be abolished by applying the PI3K inhibitor LY294002, suggesting FoxO3a not only participates in TREM2-induced anti-inflammation response, but is also involved in regulating the phenotype of microglia. Taken together, our results show that the protective functions of TREM2, both in inflammatory response and cognitive impairment as well as in the decrease of M1 phenotype microglia, are related to PI3K/AKT/FoxO3a signaling pathway in AD mice.
format Online
Article
Text
id pubmed-7655179
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Impact Journals
record_format MEDLINE/PubMed
spelling pubmed-76551792020-11-19 TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’s disease mice Wang, Yaping Lin, Yan Wang, Linhan Zhan, Hongrui Luo, Xiaoting Zeng, Yanyan Wu, Wen Zhang, Xingmei Wang, Fang Aging (Albany NY) Research Paper Triggering receptor expressed on myeloid cells 2 (TREM2) has been shown with a neuroprotective function against inflammation and neuronal injury in Alzheimer’s disease (AD). However, the TREM2 induced anti-inflammatory mechanism is still not well known. In this study it has been demonstrated that the expression of TREM2 was upregulated in hippocampus of 5xFAD mice, whereas TREM2 knock-out mediated by AAV significantly increased the levels of pro-inflammatory cytokines and aggravated cognitive defect. Additionally, FoxO3a, a downstream member of the PI3K/AKT pathway, could be activated by TREM2 defect via the PI3K/AKT signaling in 5xFAD mice. That suggests TREM2-induced protection is associated with the PI3K-FoxO3a axis. On the contrary, overexpression of TREM2 alleviated the LPS-induced inflammatory response and induced M2 phenotype microglia in vitro. This phenomenon can be abolished by applying the PI3K inhibitor LY294002, suggesting FoxO3a not only participates in TREM2-induced anti-inflammation response, but is also involved in regulating the phenotype of microglia. Taken together, our results show that the protective functions of TREM2, both in inflammatory response and cognitive impairment as well as in the decrease of M1 phenotype microglia, are related to PI3K/AKT/FoxO3a signaling pathway in AD mice. Impact Journals 2020-10-16 /pmc/articles/PMC7655179/ /pubmed/33065553 http://dx.doi.org/10.18632/aging.104104 Text en Copyright: © 2020 Wang et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Wang, Yaping
Lin, Yan
Wang, Linhan
Zhan, Hongrui
Luo, Xiaoting
Zeng, Yanyan
Wu, Wen
Zhang, Xingmei
Wang, Fang
TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’s disease mice
title TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’s disease mice
title_full TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’s disease mice
title_fullStr TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’s disease mice
title_full_unstemmed TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’s disease mice
title_short TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’s disease mice
title_sort trem2 ameliorates neuroinflammatory response and cognitive impairment via pi3k/akt/foxo3a signaling pathway in alzheimer’s disease mice
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655179/
https://www.ncbi.nlm.nih.gov/pubmed/33065553
http://dx.doi.org/10.18632/aging.104104
work_keys_str_mv AT wangyaping trem2amelioratesneuroinflammatoryresponseandcognitiveimpairmentviapi3kaktfoxo3asignalingpathwayinalzheimersdiseasemice
AT linyan trem2amelioratesneuroinflammatoryresponseandcognitiveimpairmentviapi3kaktfoxo3asignalingpathwayinalzheimersdiseasemice
AT wanglinhan trem2amelioratesneuroinflammatoryresponseandcognitiveimpairmentviapi3kaktfoxo3asignalingpathwayinalzheimersdiseasemice
AT zhanhongrui trem2amelioratesneuroinflammatoryresponseandcognitiveimpairmentviapi3kaktfoxo3asignalingpathwayinalzheimersdiseasemice
AT luoxiaoting trem2amelioratesneuroinflammatoryresponseandcognitiveimpairmentviapi3kaktfoxo3asignalingpathwayinalzheimersdiseasemice
AT zengyanyan trem2amelioratesneuroinflammatoryresponseandcognitiveimpairmentviapi3kaktfoxo3asignalingpathwayinalzheimersdiseasemice
AT wuwen trem2amelioratesneuroinflammatoryresponseandcognitiveimpairmentviapi3kaktfoxo3asignalingpathwayinalzheimersdiseasemice
AT zhangxingmei trem2amelioratesneuroinflammatoryresponseandcognitiveimpairmentviapi3kaktfoxo3asignalingpathwayinalzheimersdiseasemice
AT wangfang trem2amelioratesneuroinflammatoryresponseandcognitiveimpairmentviapi3kaktfoxo3asignalingpathwayinalzheimersdiseasemice