Soluble oligomers of amyloid-β peptide disrupt Membrane trafficking of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor contributing to early synapse dysfunction
Author
Miñano Molina, Alfredo Jesús
España, Judit
Martín, Elsa
Barneda-Zahonero, Bruna
Fadó Andrés, Rut
Solé, Montse
Trullás, Ramón
Saura, Carlos A.
Rodríguez-Álvarez, José
Publication date
2011-08-05ISSN
0021-9258
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.
Document Type
Others
Document version
Published version
Language
English
Subject (CDU)
61 - Medical sciences
616.8 - Neurology. Neuropathology. Nervous system
Keywords
Alzheimer, Malaltia d'
Fisiologia patològica
Neurotransmissió
Enfermedad de Alzheimer
Fisiopatología
Neurotransmisores
Alzheimer's disease
Pathological physiology
Neurotransmission
Pages
11
Publisher
Elsevier
Collection
286; 31
Is part of
Journal of Biological Chemistry
Citation
Miñano-Molina, Alfredo J.; España, Judit; Martín, Elsa [et al.]. Soluble oligomers of amyloid-β peptide disrupt Membrane trafficking of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor contributing to early synapse dysfunction. Journal of Biological Chemistry, 2011, 286(31), p. 27311-27321. Disponible en: <https://www.sciencedirect.com/science/article/pii/S0021925820503372?via%3Dihub>. Fecha de acceso: 3 may. 2021. DOI: 10.1074/jbc.M111.227504
Grant agreement number
info:eu-repo/grantAgreement/ES/3PN/SAF2008-0190
info:eu-repo/grantAgreement/ES/3PN/SAF2010-20925
This item appears in the following Collection(s)
- Ciències de la Salut [745]
Rights
Under a Creative Commons license. This is an Open Access article under the CC BY license.
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0/