Intracellular amyloid beta expression leads to dysregulation of the mitogen-activated protein kinase and bone morphogenetic protein-2 signaling axis

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Abstract

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.

Original languageEnglish (US)
Article numbere0191696
JournalPloS one
Volume13
Issue number2
DOIs
StatePublished - Feb 2018

Fingerprint

bone morphogenetic proteins
Bone Morphogenetic Protein 2
amyloid
Mitogen-Activated Protein Kinases
mitogen-activated protein kinase
Amyloid
Axonal Transport
Phosphorylation
Alzheimer disease
Alzheimer Disease
phosphorylation
Signal transduction
Cell Polarity
Endosomes
Amyloid Plaques
Nerve Growth Factors
Carisoprodol
synaptic transmission
endosomes
neurotrophins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

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title = "Intracellular amyloid beta expression leads to dysregulation of the mitogen-activated protein kinase and bone morphogenetic protein-2 signaling axis",
abstract = "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.",
author = "Eric Cruz and Sushil Kumar and Li Yuan and Jyothi Arikkath and Batra, {Surinder Kumar}",
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T1 - Intracellular amyloid beta expression leads to dysregulation of the mitogen-activated protein kinase and bone morphogenetic protein-2 signaling axis

AU - Cruz, Eric

AU - Kumar, Sushil

AU - Yuan, Li

AU - Arikkath, Jyothi

AU - Batra, Surinder Kumar

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