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Soluble oligomers of amyloid-beta peptide disrupt membrane trafficking of alpha-amino-3-hydroxy-5-methylisoxazole-4 propionic acid receptor (AMPAR) contributing to early synapse dysfunction
Miñano Molina, Alfredo Jesús (Universitat Autònoma de Barcelona. Institut de Neurociències)
España Agustí, Judit (Universitat Autònoma de Barcelona. Institut de Neurociències)
Martín, Elsa (Universitat Autònoma de Barcelona. Institut de Neurociències)
Barneda Zahonero, Bruna (Universitat Autònoma de Barcelona. Institut de Neurociències)
Fadó Andrés, Rut (Universitat Autònoma de Barcelona. Institut de Neurociències)
Solé Piñol, Montserrat (Universitat Autònoma de Barcelona. Institut de Neurociències)
Trullas i Oliva, Ramon (Centro de Investigación Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED))
Saura Antolín, Carlos A. (Carlos Alberto) (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular)
Rodríguez Álvarez, José (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular)

Date: 2011
Abstract: β-Amyloid (Aβ), a peptide generated from the amyloid precursor protein, is widely believed to underlie the pathophysiology of Alzheimer disease (AD). Emerging evidences suggest that soluble Aβ oligomers adversely affect synaptic function, leading to cognitive failure associated with AD. The Aβ-induced synaptic dysfunction has been attributed to the synaptic removal of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (AMPARs). However, the molecular mechanisms underlying the loss of AMPAR induced by Aβ at synapses are largely unknown. In this study we have examined the effect of Aβ oligomers on phosphorylated GluA1 at serine 845, a residue that plays an essential role in the trafficking of AMPARs toward extrasynaptic sites and the subsequent delivery to synapses during synaptic plasticity events. We found that Aβ oligomers reduce basal levels of Ser-845 phosphorylation and surface expression of AMPARs affecting AMPAR subunit composition. Aβ-induced GluA1 dephosphorylation and reduced receptor surface levels are mediated by an increase in calcium influx into neurons through ionotropic glutamate receptors and activation of the calcium-dependent phosphatase calcineurin. Moreover, Aβ oligomers block the extrasynaptic delivery of AMPARs induced by chemical synaptic potentiation. In addition, reduced levels of total and phosphorylated GluA1 are associated with initial spatial memory deficits in a transgenic mouse model of AD. These findings indicate that Aβ oligomers could act as a synaptic depressor affecting the mechanisms involved in the targeting of AMPARs to the synapses during early stages of the disease.
Note: Número d'acord de subvenció MICINN/SAF2008-01904
Note: Número d'acord de subvenció MICINN/SAF2010-20925
Note: Número d'acord de subvenció ISCIII/RD06/0026/1009
Note: Número d'acord de subvenció CIBERNED/CB06/05/0042
Rights: Tots els drets reservats.
Language: Anglès.
Document: article ; recerca ; publishedVersion
Subject: Alzheimer Disease ; Amyloid ; Calcineurin ; Calcium ; Glutamate Receptors Ionotropic (AMPA and NMDA) ; GluR1 ; Phosphorylation
Published in: The Journal of biological chemistry, Vol. 286, No. 31 (2011) , p. 543-557, ISSN 1083-351X

DOI: 10.1074/jbc.M111.227504


11 p, 1.9 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (scientific output) > Health sciences and biosciences > Institut de Neurociències (INc)
Articles > Research articles
Articles > Published articles

 Record created 2017-03-21, last modified 2019-05-23



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