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The intracellular domain of CX3CL1 regulates adult neurogenesis and Alzheimer’s amyloid pathology
The membrane-anchored CX3CL1 is best known to exert its signaling function through binding its receptor CX3CR1. This study demonstrates a novel function that CX3CL1 exerts. CX3CL1 is sequentially cleaved by α-, β-, and γ-secretase, and the released CX3CL1 intracellular domain (CX3CL1-ICD) would tran...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683996/ https://www.ncbi.nlm.nih.gov/pubmed/31209068 http://dx.doi.org/10.1084/jem.20182238 |
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author | Fan, Qingyuan Gayen, Manoshi Singh, Neeraj Gao, Fan He, Wanxia Hu, Xiangyou Tsai, Li-Huei Yan, Riqiang |
author_facet | Fan, Qingyuan Gayen, Manoshi Singh, Neeraj Gao, Fan He, Wanxia Hu, Xiangyou Tsai, Li-Huei Yan, Riqiang |
author_sort | Fan, Qingyuan |
collection | PubMed |
description | The membrane-anchored CX3CL1 is best known to exert its signaling function through binding its receptor CX3CR1. This study demonstrates a novel function that CX3CL1 exerts. CX3CL1 is sequentially cleaved by α-, β-, and γ-secretase, and the released CX3CL1 intracellular domain (CX3CL1-ICD) would translocate into the cell nucleus to alter gene expression due to this back-signaling function. Amyloid deposition and neuronal loss were significantly reduced when membrane-anchored CX3CL1 C-terminal fragment (CX3CL1-ct) was overexpressed in Alzheimer’s 5xFAD mouse model. The reversal of neuronal loss in 5xFAD can be attributed to increased neurogenesis by CX3CL1-ICD, as revealed by morphological and unbiased RNA-sequencing analyses. Mechanistically, this CX3CL1 back-signal likely enhances developmental and adult neurogenesis through the TGFβ2/3-Smad2/3 pathway and other genes important for neurogenesis. Induction of CX3CL1 back-signaling may not only be a promising novel mechanism to replenish neuronal loss but also for reducing amyloid deposition for Alzheimer’s treatment. |
format | Online Article Text |
id | pubmed-6683996 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-66839962020-02-05 The intracellular domain of CX3CL1 regulates adult neurogenesis and Alzheimer’s amyloid pathology Fan, Qingyuan Gayen, Manoshi Singh, Neeraj Gao, Fan He, Wanxia Hu, Xiangyou Tsai, Li-Huei Yan, Riqiang J Exp Med Research Articles The membrane-anchored CX3CL1 is best known to exert its signaling function through binding its receptor CX3CR1. This study demonstrates a novel function that CX3CL1 exerts. CX3CL1 is sequentially cleaved by α-, β-, and γ-secretase, and the released CX3CL1 intracellular domain (CX3CL1-ICD) would translocate into the cell nucleus to alter gene expression due to this back-signaling function. Amyloid deposition and neuronal loss were significantly reduced when membrane-anchored CX3CL1 C-terminal fragment (CX3CL1-ct) was overexpressed in Alzheimer’s 5xFAD mouse model. The reversal of neuronal loss in 5xFAD can be attributed to increased neurogenesis by CX3CL1-ICD, as revealed by morphological and unbiased RNA-sequencing analyses. Mechanistically, this CX3CL1 back-signal likely enhances developmental and adult neurogenesis through the TGFβ2/3-Smad2/3 pathway and other genes important for neurogenesis. Induction of CX3CL1 back-signaling may not only be a promising novel mechanism to replenish neuronal loss but also for reducing amyloid deposition for Alzheimer’s treatment. Rockefeller University Press 2019-08-05 2019-06-17 /pmc/articles/PMC6683996/ /pubmed/31209068 http://dx.doi.org/10.1084/jem.20182238 Text en © 2019 Fan 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 Fan, Qingyuan Gayen, Manoshi Singh, Neeraj Gao, Fan He, Wanxia Hu, Xiangyou Tsai, Li-Huei Yan, Riqiang The intracellular domain of CX3CL1 regulates adult neurogenesis and Alzheimer’s amyloid pathology |
title | The intracellular domain of CX3CL1 regulates adult neurogenesis and Alzheimer’s amyloid pathology |
title_full | The intracellular domain of CX3CL1 regulates adult neurogenesis and Alzheimer’s amyloid pathology |
title_fullStr | The intracellular domain of CX3CL1 regulates adult neurogenesis and Alzheimer’s amyloid pathology |
title_full_unstemmed | The intracellular domain of CX3CL1 regulates adult neurogenesis and Alzheimer’s amyloid pathology |
title_short | The intracellular domain of CX3CL1 regulates adult neurogenesis and Alzheimer’s amyloid pathology |
title_sort | intracellular domain of cx3cl1 regulates adult neurogenesis and alzheimer’s amyloid pathology |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683996/ https://www.ncbi.nlm.nih.gov/pubmed/31209068 http://dx.doi.org/10.1084/jem.20182238 |
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