title: 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.
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.
authors.affiliation: Institut de Neurociencies and Departament de Bioquímica i Biología Molecular, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona.
authors.forename: Alfredo J
authors.initials: AJ
authors.lastname: Miñano-Molina
authors.forename: Judit
authors.initials: J
authors.lastname: España
authors.forename: Elsa
authors.initials: E
authors.lastname: Martín
authors.forename: Bruna
authors.initials: B
authors.lastname: Barneda-Zahonero
authors.forename: Rut
authors.initials: R
authors.lastname: Fadó
authors.forename: Montse
authors.initials: M
authors.lastname: Solé
authors.forename: Ramón
authors.initials: R
authors.lastname: Trullás
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Saura
authors.forename: José
authors.initials: J
authors.lastname: Rodríguez-Alvarez
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001704:Biopolymers / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D021381:Protein Transport; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D001704:Biopolymers; D018091:Receptors, AMPA