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

␤-Amyloid (A␤), a peptide generated from the amyloid precursor protein, is widely believed to underlie the pathophysiology of Alzheimer disease (AD). Emerging evidences suggest that soluble A␤ oligomers adversely affect synaptic function, leading to cognitive failure associated with AD. The A␤-induced synaptic dysfunction has been attributed to the synaptic removal of ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (AMPARs). However, the molecular mechanisms underlying the loss of AMPAR induced by A␤ at synapses are largely unknown. In this study we have examined the effect of A␤ 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 A␤ oligomers reduce basal levels of Ser-845 phosphorylation and surface expression of AMPARs affecting AMPAR subunit composition. A␤-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, A␤ 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 A␤ 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. Alzheimer disease (AD)2 is an age-dependent neurodegenerative disorder and the first cause of dementia in the elderly.AD is thought to involve changes in excitatory synaptic transmission in brain regions that are critical for cognitive function and memory encoding (1). Synaptic dysfunction in AD occurs apparently long before synapse and neuron loss is observed. Several findings suggest that it is caused by accumulation of soluble oligomers of amyloid-␤ (oA␤) peptides, also referred as amyloid-␤-derived diffusible ligands (1-3) that have been described as potently toxic species for synapses (4 -6).Excitatory synaptic transmission is tightly regulated by total number and activation of AMPA receptors (AMPARs) present at the synapse. The NMDA receptor (NMDAR) has a central role in synaptic plasticity events, such as long term potentiation (LTP) or long term depression (LTD), depending on the extent of the [Ca 2ϩ

Extracellular Alpha-Synuclein Oligomers Modulate Synaptic Transmission and Impair LTP Via NMDA-Receptor Activation

“…The toxicity induced by a-syn oligomers might be a consequence of enhanced Ca 2ϩ influx through NMDA receptors (Kelly and Ferreira, 2006;Martin et al, 2012). Recently, it was shown that soluble A␤ oligomers affect GluR1 phosphorylation and AMPA receptor trafficking through increased calcium influx and activation of calcium-dependent phosphatase calcineurin (Miñano-Molina et al, 2011). Our data fully support a similar mechanism for a-syn oligomers.…”

Aβ42 oligomers selectively disrupt neuronal calcium release

“…It is worth noting that we avoided preparing Ab42o in F12 medium, a frequently employed procedure (De Felice et al, 2007;Lambert et al, 1998;Mairet-Coello et al, 2013;Minano-Molina et al, 2011;Resende et al, 2008;Zhao et al, 2010) given that aged F12 medium by itself, at the same final dilution (1:100), causes neuronal Ca 2þ rises (Zempel et al, 2010). Concerning the characteristics of the Ab42 preparations, the presence of heat-sensitive Ab-derived diffusible ligands was routinely checked by Western blots (Fig.…”

Neurogranin restores amyloid β-mediated synaptic transmission and long-term potentiation deficits

“…It is now widely believed that the accumulation of soluble Aβ is central to the pathogenesis of the disease (Selkoe, 2000). Soluble Aβ oligomers have been shown to induce many of the deficits associated with AD (Shankar et al, 2008;Logan et al, 2011;Miñano-Molina et al, 2011;Reese et al, 2011;Tan et al, 2011;Ferreira et al, 2012). The Aβ oligomers disrupt synaptic function by causing synaptic depression (Kamenetz et al, 2003b;Hsieh et al, 2006b;Santos-Torres et al, 2007;Li et al, 2009;Cerpa et al, 2010;Kessels et al, 2010a;Kessels et al, 2013;Talantova et al, 2013;Tamburri et al, 2013) and blocking long-term potentiation (LTP) (Walsh et al, 2002;Rowan et al, 2005;Shankar et al, 2008;Rammes et al, 2011;Wang et al, 2012;Sivanesan et al, 2013), a cellular model for learning and memory.…”