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Alzheimer Amyloid-β Oligomer Bound to Post-Synaptic Prion Protein Activates Fyn to Impair Neurons

Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer’s disease (AD) pathophysiology. Cellular Prion Protein (PrP(C)) selectively binds oligomeric Aβ and can mediate AD-related phenotypes. Here, we examined the specificity, distribution and signaling from Aβ/PrP complexes, seeking to explain...

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Autores principales: Um, Ji Won, Nygaard, Haakon B., Heiss, Jacqueline K., Kostylev, Mikhail A., Stagi, Massimiliano, Vortmeyer, Alexander, Wisniewski, Thomas, Gunther, Erik C., Strittmatter, Stephen M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431439/
https://www.ncbi.nlm.nih.gov/pubmed/22820466
http://dx.doi.org/10.1038/nn.3178
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author Um, Ji Won
Nygaard, Haakon B.
Heiss, Jacqueline K.
Kostylev, Mikhail A.
Stagi, Massimiliano
Vortmeyer, Alexander
Wisniewski, Thomas
Gunther, Erik C.
Strittmatter, Stephen M.
author_facet Um, Ji Won
Nygaard, Haakon B.
Heiss, Jacqueline K.
Kostylev, Mikhail A.
Stagi, Massimiliano
Vortmeyer, Alexander
Wisniewski, Thomas
Gunther, Erik C.
Strittmatter, Stephen M.
author_sort Um, Ji Won
collection PubMed
description Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer’s disease (AD) pathophysiology. Cellular Prion Protein (PrP(C)) selectively binds oligomeric Aβ and can mediate AD-related phenotypes. Here, we examined the specificity, distribution and signaling from Aβ/PrP complexes, seeking to explain how they might alter the function of NMDA receptors in neurons. PrP(C) is enriched in post-synaptic densities, and Aβ/PrP(C) interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from human AD brain interact with PrP(C) to activate Fyn. Aβ engagement of PrP(C)/Fyn signaling yields phosphorylation of the NR2B subunit of NMDA-receptors, which is coupled to an initial increase and then loss of surface NMDA-receptors. Aβ-induced LDH release and dendritic spine loss require both PrP(C) and Fyn, and human familial AD transgene-induced convulsive seizures do not occur in mice lacking PrP(C). These results delineate an Aβ oligomer signal transduction pathway requiring PrP(C) and Fyn to alter synaptic function with relevance to AD.
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spelling pubmed-34314392013-03-01 Alzheimer Amyloid-β Oligomer Bound to Post-Synaptic Prion Protein Activates Fyn to Impair Neurons Um, Ji Won Nygaard, Haakon B. Heiss, Jacqueline K. Kostylev, Mikhail A. Stagi, Massimiliano Vortmeyer, Alexander Wisniewski, Thomas Gunther, Erik C. Strittmatter, Stephen M. Nat Neurosci Article Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer’s disease (AD) pathophysiology. Cellular Prion Protein (PrP(C)) selectively binds oligomeric Aβ and can mediate AD-related phenotypes. Here, we examined the specificity, distribution and signaling from Aβ/PrP complexes, seeking to explain how they might alter the function of NMDA receptors in neurons. PrP(C) is enriched in post-synaptic densities, and Aβ/PrP(C) interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from human AD brain interact with PrP(C) to activate Fyn. Aβ engagement of PrP(C)/Fyn signaling yields phosphorylation of the NR2B subunit of NMDA-receptors, which is coupled to an initial increase and then loss of surface NMDA-receptors. Aβ-induced LDH release and dendritic spine loss require both PrP(C) and Fyn, and human familial AD transgene-induced convulsive seizures do not occur in mice lacking PrP(C). These results delineate an Aβ oligomer signal transduction pathway requiring PrP(C) and Fyn to alter synaptic function with relevance to AD. 2012-07-22 2012-09 /pmc/articles/PMC3431439/ /pubmed/22820466 http://dx.doi.org/10.1038/nn.3178 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Um, Ji Won
Nygaard, Haakon B.
Heiss, Jacqueline K.
Kostylev, Mikhail A.
Stagi, Massimiliano
Vortmeyer, Alexander
Wisniewski, Thomas
Gunther, Erik C.
Strittmatter, Stephen M.
Alzheimer Amyloid-β Oligomer Bound to Post-Synaptic Prion Protein Activates Fyn to Impair Neurons
title Alzheimer Amyloid-β Oligomer Bound to Post-Synaptic Prion Protein Activates Fyn to Impair Neurons
title_full Alzheimer Amyloid-β Oligomer Bound to Post-Synaptic Prion Protein Activates Fyn to Impair Neurons
title_fullStr Alzheimer Amyloid-β Oligomer Bound to Post-Synaptic Prion Protein Activates Fyn to Impair Neurons
title_full_unstemmed Alzheimer Amyloid-β Oligomer Bound to Post-Synaptic Prion Protein Activates Fyn to Impair Neurons
title_short Alzheimer Amyloid-β Oligomer Bound to Post-Synaptic Prion Protein Activates Fyn to Impair Neurons
title_sort alzheimer amyloid-β oligomer bound to post-synaptic prion protein activates fyn to impair neurons
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431439/
https://www.ncbi.nlm.nih.gov/pubmed/22820466
http://dx.doi.org/10.1038/nn.3178
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