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Amyloid-β interrupts canonical Sonic hedgehog signaling by distorting primary cilia structure

BACKGROUND: Primary cilia are small non-motile microtubule and cell membrane protrusions expressed on most vertebrate cells, including cortical and hippocampal neurons. These small organelles serve as sensory structures sampling the extracellular environment and reprogramming the transcriptional mac...

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Autores principales: Vorobyeva, Anna G., Saunders, Aleister J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098584/
https://www.ncbi.nlm.nih.gov/pubmed/30140428
http://dx.doi.org/10.1186/s13630-018-0059-y
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author Vorobyeva, Anna G.
Saunders, Aleister J.
author_facet Vorobyeva, Anna G.
Saunders, Aleister J.
author_sort Vorobyeva, Anna G.
collection PubMed
description BACKGROUND: Primary cilia are small non-motile microtubule and cell membrane protrusions expressed on most vertebrate cells, including cortical and hippocampal neurons. These small organelles serve as sensory structures sampling the extracellular environment and reprogramming the transcriptional machinery in response to environmental change. Primary cilia are decorated with a variety of receptor proteins and are necessary for specific signaling cascades such as the Sonic hedgehog (Shh) pathway. Disrupting cilia structure or function results in a spectrum of diseases collectively referred to as ciliopathies. Common to human ciliopathies is cognitive impairment, a symptom also observed in Alzheimer’s disease (AD). One hallmark of AD is accumulation of senile plaques composed of neurotoxic Amyloid-β (Aβ) peptide. The Aβ peptide is generated by the proteolytic cleavage of the amyloid precursor protein (APP). We set out to determine if Aβ affects primary cilia structure and the Shh signaling cascade. METHODS: We utilized in vitro cell-based assays in combination with fluorescent confocal microscopy to address our study goals. Shh signaling and cilia structure was studied using two different cell lines, mouse NIH3T3 and human HeLa cells. To investigate how Aβ levels affect Shh signaling and cilia structure in these cells, we utilized naturally secreted Aβ as well as synthetic Aβ. Effects on Shh signaling were assessed by luciferase activity while cilia structure was analyzed by fluorescent microscopy. RESULTS: Here, we report that APP localizes to primary cilia and Aβ treatment results in distorted primary cilia structure. In addition, we demonstrate that Aβ treatment interrupts canonical Shh signal transduction. CONCLUSIONS: Overall, our study illustrates that Aβ can alter primary cilia structure suggesting that elevated Aβ levels, like those observed in AD patients, could have similar effects on neuronal primary cilia in the brain. Additionally, our study suggests that Aβ impairs the Shh signaling pathway. Together our findings shed light on two novel targets for future AD therapeutics. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13630-018-0059-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-60985842018-08-23 Amyloid-β interrupts canonical Sonic hedgehog signaling by distorting primary cilia structure Vorobyeva, Anna G. Saunders, Aleister J. Cilia Research BACKGROUND: Primary cilia are small non-motile microtubule and cell membrane protrusions expressed on most vertebrate cells, including cortical and hippocampal neurons. These small organelles serve as sensory structures sampling the extracellular environment and reprogramming the transcriptional machinery in response to environmental change. Primary cilia are decorated with a variety of receptor proteins and are necessary for specific signaling cascades such as the Sonic hedgehog (Shh) pathway. Disrupting cilia structure or function results in a spectrum of diseases collectively referred to as ciliopathies. Common to human ciliopathies is cognitive impairment, a symptom also observed in Alzheimer’s disease (AD). One hallmark of AD is accumulation of senile plaques composed of neurotoxic Amyloid-β (Aβ) peptide. The Aβ peptide is generated by the proteolytic cleavage of the amyloid precursor protein (APP). We set out to determine if Aβ affects primary cilia structure and the Shh signaling cascade. METHODS: We utilized in vitro cell-based assays in combination with fluorescent confocal microscopy to address our study goals. Shh signaling and cilia structure was studied using two different cell lines, mouse NIH3T3 and human HeLa cells. To investigate how Aβ levels affect Shh signaling and cilia structure in these cells, we utilized naturally secreted Aβ as well as synthetic Aβ. Effects on Shh signaling were assessed by luciferase activity while cilia structure was analyzed by fluorescent microscopy. RESULTS: Here, we report that APP localizes to primary cilia and Aβ treatment results in distorted primary cilia structure. In addition, we demonstrate that Aβ treatment interrupts canonical Shh signal transduction. CONCLUSIONS: Overall, our study illustrates that Aβ can alter primary cilia structure suggesting that elevated Aβ levels, like those observed in AD patients, could have similar effects on neuronal primary cilia in the brain. Additionally, our study suggests that Aβ impairs the Shh signaling pathway. Together our findings shed light on two novel targets for future AD therapeutics. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13630-018-0059-y) contains supplementary material, which is available to authorized users. BioMed Central 2018-08-17 /pmc/articles/PMC6098584/ /pubmed/30140428 http://dx.doi.org/10.1186/s13630-018-0059-y Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Vorobyeva, Anna G.
Saunders, Aleister J.
Amyloid-β interrupts canonical Sonic hedgehog signaling by distorting primary cilia structure
title Amyloid-β interrupts canonical Sonic hedgehog signaling by distorting primary cilia structure
title_full Amyloid-β interrupts canonical Sonic hedgehog signaling by distorting primary cilia structure
title_fullStr Amyloid-β interrupts canonical Sonic hedgehog signaling by distorting primary cilia structure
title_full_unstemmed Amyloid-β interrupts canonical Sonic hedgehog signaling by distorting primary cilia structure
title_short Amyloid-β interrupts canonical Sonic hedgehog signaling by distorting primary cilia structure
title_sort amyloid-β interrupts canonical sonic hedgehog signaling by distorting primary cilia structure
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098584/
https://www.ncbi.nlm.nih.gov/pubmed/30140428
http://dx.doi.org/10.1186/s13630-018-0059-y
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