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
Autor/a
Miñano Molina, Alfredo Jesús
España, Judit
Martín, Elsa
Barneda-Zahonero, Bruna
Fadó Andrés, Rut
Solé, Montse
Trullás, Ramón
Saura, Carlos A.
Rodríguez-Álvarez, José
Data de publicació
2011-08-05ISSN
0021-9258
Resum
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.
Tipus de document
Altres
Versió del document
Versió publicada
Llengua
English
Matèries (CDU)
61 - Medicina
616.8 - Neurologia. Neuropatologia. Sistema nerviós
Paraules clau
Alzheimer, Malaltia d'
Fisiologia patològica
Neurotransmissió
Enfermedad de Alzheimer
Fisiopatología
Neurotransmisores
Alzheimer's disease
Pathological physiology
Neurotransmission
Pàgines
11
Publicat per
Elsevier
Col·lecció
286; 31
Publicat a
Journal of Biological Chemistry
Citació
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
Número de l'acord de la subvenció
info:eu-repo/grantAgreement/ES/3PN/SAF2008-0190
info:eu-repo/grantAgreement/ES/3PN/SAF2010-20925
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Drets
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