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SNX8 Enhances Non-amyloidogenic APP Trafficking and Attenuates Aβ Accumulation and Memory Deficits in an AD Mouse

Dysregulation of various APP trafficking components in the endosome has been previously implicated in Alzheimer’s disease (AD). Although single nucleotide polymorphisms within the gene locus encoding the endosomal component, SNX8 have been previously associated with AD, how SNX8 levels are altered a...

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Autores principales: Xie, Yongzhuang, Niu, Mengxi, Ji, Chengxiang, Huang, Timothy Y., Zhang, Cuilin, Tian, Ye, Shi, Zhun, Wang, Chen, Zhao, Yingjun, Luo, Hong, Can, Dan, Xu, Huaxi, Zhang, Yun-wu, Zhang, Xian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743354/
https://www.ncbi.nlm.nih.gov/pubmed/31551717
http://dx.doi.org/10.3389/fncel.2019.00410
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author Xie, Yongzhuang
Niu, Mengxi
Ji, Chengxiang
Huang, Timothy Y.
Zhang, Cuilin
Tian, Ye
Shi, Zhun
Wang, Chen
Zhao, Yingjun
Luo, Hong
Can, Dan
Xu, Huaxi
Zhang, Yun-wu
Zhang, Xian
author_facet Xie, Yongzhuang
Niu, Mengxi
Ji, Chengxiang
Huang, Timothy Y.
Zhang, Cuilin
Tian, Ye
Shi, Zhun
Wang, Chen
Zhao, Yingjun
Luo, Hong
Can, Dan
Xu, Huaxi
Zhang, Yun-wu
Zhang, Xian
author_sort Xie, Yongzhuang
collection PubMed
description Dysregulation of various APP trafficking components in the endosome has been previously implicated in Alzheimer’s disease (AD). Although single nucleotide polymorphisms within the gene locus encoding the endosomal component, SNX8 have been previously associated with AD, how SNX8 levels are altered and its contribution to AD onset is currently unknown. Here, we observe decreased expression of SNX8 in human AD and AD mouse brain. SNX8 predominantly localized to early and late endosomes, where SNX8 overexpression enhanced total APP levels, cell surface APP distribution and consequent soluble APPα cleavage. SNX8 depletion resulted in elevated β-amyloid (Aβ) levels, while SNX8 overexpression reduced Aβ levels in cells and in an APP/PS1 AD mouse model. Importantly, SNX8 overexpression rescued cognitive impairment in APP/PS1 mice. Together, these results implicate a neuroprotective role for SNX8 in enhancing non-amyloidogenic APP trafficking and processing pathways. Given that endosomal dysfunction is an early event in AD, restoration of dysfunctional endosomal components such as SNX8 may be beneficial in future therapeutic strategies.
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spelling pubmed-67433542019-09-24 SNX8 Enhances Non-amyloidogenic APP Trafficking and Attenuates Aβ Accumulation and Memory Deficits in an AD Mouse Xie, Yongzhuang Niu, Mengxi Ji, Chengxiang Huang, Timothy Y. Zhang, Cuilin Tian, Ye Shi, Zhun Wang, Chen Zhao, Yingjun Luo, Hong Can, Dan Xu, Huaxi Zhang, Yun-wu Zhang, Xian Front Cell Neurosci Neuroscience Dysregulation of various APP trafficking components in the endosome has been previously implicated in Alzheimer’s disease (AD). Although single nucleotide polymorphisms within the gene locus encoding the endosomal component, SNX8 have been previously associated with AD, how SNX8 levels are altered and its contribution to AD onset is currently unknown. Here, we observe decreased expression of SNX8 in human AD and AD mouse brain. SNX8 predominantly localized to early and late endosomes, where SNX8 overexpression enhanced total APP levels, cell surface APP distribution and consequent soluble APPα cleavage. SNX8 depletion resulted in elevated β-amyloid (Aβ) levels, while SNX8 overexpression reduced Aβ levels in cells and in an APP/PS1 AD mouse model. Importantly, SNX8 overexpression rescued cognitive impairment in APP/PS1 mice. Together, these results implicate a neuroprotective role for SNX8 in enhancing non-amyloidogenic APP trafficking and processing pathways. Given that endosomal dysfunction is an early event in AD, restoration of dysfunctional endosomal components such as SNX8 may be beneficial in future therapeutic strategies. Frontiers Media S.A. 2019-09-06 /pmc/articles/PMC6743354/ /pubmed/31551717 http://dx.doi.org/10.3389/fncel.2019.00410 Text en Copyright © 2019 Xie, Niu, Ji, Huang, Zhang, Tian, Shi, Wang, Zhao, Luo, Can, Xu, Zhang and Zhang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Xie, Yongzhuang
Niu, Mengxi
Ji, Chengxiang
Huang, Timothy Y.
Zhang, Cuilin
Tian, Ye
Shi, Zhun
Wang, Chen
Zhao, Yingjun
Luo, Hong
Can, Dan
Xu, Huaxi
Zhang, Yun-wu
Zhang, Xian
SNX8 Enhances Non-amyloidogenic APP Trafficking and Attenuates Aβ Accumulation and Memory Deficits in an AD Mouse
title SNX8 Enhances Non-amyloidogenic APP Trafficking and Attenuates Aβ Accumulation and Memory Deficits in an AD Mouse
title_full SNX8 Enhances Non-amyloidogenic APP Trafficking and Attenuates Aβ Accumulation and Memory Deficits in an AD Mouse
title_fullStr SNX8 Enhances Non-amyloidogenic APP Trafficking and Attenuates Aβ Accumulation and Memory Deficits in an AD Mouse
title_full_unstemmed SNX8 Enhances Non-amyloidogenic APP Trafficking and Attenuates Aβ Accumulation and Memory Deficits in an AD Mouse
title_short SNX8 Enhances Non-amyloidogenic APP Trafficking and Attenuates Aβ Accumulation and Memory Deficits in an AD Mouse
title_sort snx8 enhances non-amyloidogenic app trafficking and attenuates aβ accumulation and memory deficits in an ad mouse
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743354/
https://www.ncbi.nlm.nih.gov/pubmed/31551717
http://dx.doi.org/10.3389/fncel.2019.00410
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