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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...

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Autores principales: Fan, Qingyuan, Gayen, Manoshi, Singh, Neeraj, Gao, Fan, He, Wanxia, Hu, Xiangyou, Tsai, Li-Huei, Yan, Riqiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
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.
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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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