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Intracellular amyloid beta expression leads to dysregulation of the mitogen-activated protein kinase and bone morphogenetic protein-2 signaling axis
Alzheimer’s disease (AD) is a neurodegenerative syndrome classically depicted by the parenchymal accumulation of extracellular amyloid beta plaques. However, recent findings suggest intraneuronal amyloid beta (iAβ(1–42)) accumulation precedes extracellular deposition. Furthermore, the pathologic inc...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823380/ https://www.ncbi.nlm.nih.gov/pubmed/29470488 http://dx.doi.org/10.1371/journal.pone.0191696 |
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author | Cruz, Eric Kumar, Sushil Yuan, Li Arikkath, Jyothi Batra, Surinder K. |
author_facet | Cruz, Eric Kumar, Sushil Yuan, Li Arikkath, Jyothi Batra, Surinder K. |
author_sort | Cruz, Eric |
collection | PubMed |
description | Alzheimer’s disease (AD) is a neurodegenerative syndrome classically depicted by the parenchymal accumulation of extracellular amyloid beta plaques. However, recent findings suggest intraneuronal amyloid beta (iAβ(1–42)) accumulation precedes extracellular deposition. Furthermore, the pathologic increase in iAβ(1–42) has been implicated in dysregulation of cellular mechanisms critically important in axonal transport. Owing to neuronal cell polarity, retrograde and anterograde axonal transport are essential trafficking mechanism necessary to convey membrane bound neurotransmitters, neurotrophins, and endosomes between soma and synaptic interfaces. Although iAβ(1–42) disruption of axonal transport has been implicated in dysregulation of neuronal synaptic transmission, the role of iAβ(1–42) and its influence on signal transduction involving the mitogen-activated protein kinase (MAPK) and morphogenetic signaling axis are unknown. Our biochemical characterization of intracellular amyloid beta accumulation on MAPK and morphogenetic signaling have revealed increased iAβ(1–42) expression leads to significant reduction in ERK 1/2 phosphorylation and increased bone morphogenetic protein 2 dependent Smad 1/5/8 phosphorylation. Furthermore, rescue of iAβ(1–42) mediated attenuation of MAPK signaling can be accomplished with the small molecule PLX4032 as a downstream enhancer of the MAPK pathway. Consequently, our observations regarding the dysregulation of these gatekeepers of neuronal viability may have important implications in understanding the iAβ(1–42) mediated effects observed in AD. |
format | Online Article Text |
id | pubmed-5823380 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-58233802018-03-15 Intracellular amyloid beta expression leads to dysregulation of the mitogen-activated protein kinase and bone morphogenetic protein-2 signaling axis Cruz, Eric Kumar, Sushil Yuan, Li Arikkath, Jyothi Batra, Surinder K. PLoS One Research Article Alzheimer’s disease (AD) is a neurodegenerative syndrome classically depicted by the parenchymal accumulation of extracellular amyloid beta plaques. However, recent findings suggest intraneuronal amyloid beta (iAβ(1–42)) accumulation precedes extracellular deposition. Furthermore, the pathologic increase in iAβ(1–42) has been implicated in dysregulation of cellular mechanisms critically important in axonal transport. Owing to neuronal cell polarity, retrograde and anterograde axonal transport are essential trafficking mechanism necessary to convey membrane bound neurotransmitters, neurotrophins, and endosomes between soma and synaptic interfaces. Although iAβ(1–42) disruption of axonal transport has been implicated in dysregulation of neuronal synaptic transmission, the role of iAβ(1–42) and its influence on signal transduction involving the mitogen-activated protein kinase (MAPK) and morphogenetic signaling axis are unknown. Our biochemical characterization of intracellular amyloid beta accumulation on MAPK and morphogenetic signaling have revealed increased iAβ(1–42) expression leads to significant reduction in ERK 1/2 phosphorylation and increased bone morphogenetic protein 2 dependent Smad 1/5/8 phosphorylation. Furthermore, rescue of iAβ(1–42) mediated attenuation of MAPK signaling can be accomplished with the small molecule PLX4032 as a downstream enhancer of the MAPK pathway. Consequently, our observations regarding the dysregulation of these gatekeepers of neuronal viability may have important implications in understanding the iAβ(1–42) mediated effects observed in AD. Public Library of Science 2018-02-22 /pmc/articles/PMC5823380/ /pubmed/29470488 http://dx.doi.org/10.1371/journal.pone.0191696 Text en © 2018 Cruz et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Cruz, Eric Kumar, Sushil Yuan, Li Arikkath, Jyothi Batra, Surinder K. Intracellular amyloid beta expression leads to dysregulation of the mitogen-activated protein kinase and bone morphogenetic protein-2 signaling axis |
title | Intracellular amyloid beta expression leads to dysregulation of the mitogen-activated protein kinase and bone morphogenetic protein-2 signaling axis |
title_full | Intracellular amyloid beta expression leads to dysregulation of the mitogen-activated protein kinase and bone morphogenetic protein-2 signaling axis |
title_fullStr | Intracellular amyloid beta expression leads to dysregulation of the mitogen-activated protein kinase and bone morphogenetic protein-2 signaling axis |
title_full_unstemmed | Intracellular amyloid beta expression leads to dysregulation of the mitogen-activated protein kinase and bone morphogenetic protein-2 signaling axis |
title_short | Intracellular amyloid beta expression leads to dysregulation of the mitogen-activated protein kinase and bone morphogenetic protein-2 signaling axis |
title_sort | intracellular amyloid beta expression leads to dysregulation of the mitogen-activated protein kinase and bone morphogenetic protein-2 signaling axis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823380/ https://www.ncbi.nlm.nih.gov/pubmed/29470488 http://dx.doi.org/10.1371/journal.pone.0191696 |
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