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Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers
A pathological hallmark of Alzheimer’s disease (AD) is an accumulation of insoluble plaque containing the amyloid-β peptide (Aβ) of 40–42 aa residues1. Prefibrillar, soluble oligomers of Aβ have been recognized to be early and key intermediates in AD-related synaptic dysfunction2–9. At nanomolar con...
Autores principales: | , , , , |
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Formato: | Texto |
Lenguaje: | English |
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2009
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748841/ https://www.ncbi.nlm.nih.gov/pubmed/19242475 http://dx.doi.org/10.1038/nature07761 |
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author | Laurén, Juha Gimbel, David A. Nygaard, Haakon B. Gilbert, John W. Strittmatter, Stephen M. |
author_facet | Laurén, Juha Gimbel, David A. Nygaard, Haakon B. Gilbert, John W. Strittmatter, Stephen M. |
author_sort | Laurén, Juha |
collection | PubMed |
description | A pathological hallmark of Alzheimer’s disease (AD) is an accumulation of insoluble plaque containing the amyloid-β peptide (Aβ) of 40–42 aa residues1. Prefibrillar, soluble oligomers of Aβ have been recognized to be early and key intermediates in AD-related synaptic dysfunction2–9. At nanomolar concentrations, soluble Aβ-oligomers block hippocampal long-term potentiation7, cause dendritic spine retraction from pyramidal cells5,8 and impair rodent spatial memory2. Soluble Aβ-oligomers have been prepared from chemical syntheses, from transfected cell culture supernatants, from transgenic mouse brain and from human AD brain2,4,7,9. Together, these data imply a high affinity cell surface receptor for soluble Aβ-oligomers on neurons, one that is central to the pathophysiological process in AD. Here, we identify the cellular Prion Protein (PrP(C)) as an Aβ-oligomer receptor by expression cloning. Aβ-oligomers bind with nanomolar affinity to PrP(C), but the interaction does not require the infectious PrP(Sc) conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the Aβ-oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent Aβ-oligomer binding to PrP(C) and rescue synaptic plasticity in hippocampal slices from oligomeric β. Thus, PrP(C) is a mediator of Aβoligomer induced synaptic dysfunction, and PrP(C)-specific pharmaceuticals may have therapeutic potential for Alzheimer’s disease. |
format | Text |
id | pubmed-2748841 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
record_format | MEDLINE/PubMed |
spelling | pubmed-27488412009-09-22 Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers Laurén, Juha Gimbel, David A. Nygaard, Haakon B. Gilbert, John W. Strittmatter, Stephen M. Nature Article A pathological hallmark of Alzheimer’s disease (AD) is an accumulation of insoluble plaque containing the amyloid-β peptide (Aβ) of 40–42 aa residues1. Prefibrillar, soluble oligomers of Aβ have been recognized to be early and key intermediates in AD-related synaptic dysfunction2–9. At nanomolar concentrations, soluble Aβ-oligomers block hippocampal long-term potentiation7, cause dendritic spine retraction from pyramidal cells5,8 and impair rodent spatial memory2. Soluble Aβ-oligomers have been prepared from chemical syntheses, from transfected cell culture supernatants, from transgenic mouse brain and from human AD brain2,4,7,9. Together, these data imply a high affinity cell surface receptor for soluble Aβ-oligomers on neurons, one that is central to the pathophysiological process in AD. Here, we identify the cellular Prion Protein (PrP(C)) as an Aβ-oligomer receptor by expression cloning. Aβ-oligomers bind with nanomolar affinity to PrP(C), but the interaction does not require the infectious PrP(Sc) conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the Aβ-oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent Aβ-oligomer binding to PrP(C) and rescue synaptic plasticity in hippocampal slices from oligomeric β. Thus, PrP(C) is a mediator of Aβoligomer induced synaptic dysfunction, and PrP(C)-specific pharmaceuticals may have therapeutic potential for Alzheimer’s disease. 2009-02-26 /pmc/articles/PMC2748841/ /pubmed/19242475 http://dx.doi.org/10.1038/nature07761 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download 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 Laurén, Juha Gimbel, David A. Nygaard, Haakon B. Gilbert, John W. Strittmatter, Stephen M. Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers |
title | Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers |
title_full | Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers |
title_fullStr | Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers |
title_full_unstemmed | Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers |
title_short | Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers |
title_sort | cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748841/ https://www.ncbi.nlm.nih.gov/pubmed/19242475 http://dx.doi.org/10.1038/nature07761 |
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