Inhibition of Calcineurin-mediated Endocytosis and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Prevents Amyloid β Oligomer-induced Synaptic Disruption

Zhao, Weiqin; Santini, Francesca; Breese, Robert; Ross, Dave; Zhang, Xiaohua Douglas; Stone, David J.; Ferrer, Marc; Townsend, Matthew; Wolfe, Abigail; Seager, Matthew A.; Kinney, Gene G.; Shughrue, Paul J.; Ray, William J.

doi:10.1074/jbc.m109.057182

Cited by 173 publications

(179 citation statements)

References 84 publications

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“…Other studies have focused on the functional interactions between A␤ peptide and glutamate receptors (Decker et al, 2010b;Hu et al, 2009;Texidó et al, 2011;Zhao et al, 2010) or have attempted to reinforce neuronal defenses through the neurotrophic effects of growth factors or membrane lipids such as docosahexaenoic acid (Ma et al, 2009). Many NMDA receptor modulators have been characterized and are potential therapeutics for Alzheimer's disease.…”

Section: Discussionmentioning

confidence: 99%

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Desbène

Malaplate-Armand

Youssef

et al. 2012

Neurobiology of Aging

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Soluble beta-amyloid (A␤) oligomers are considered to putatively play a critical role in the early synapse loss and cognitive impairment observed in Alzheimer's disease. We previously demonstrated that A␤ oligomers activate cytosolic phospholipase A 2 (cPLA 2 ), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA 2 gene inactivation prevented the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels noticed upon a single intracerebroventricular injection of A␤ oligomers in wild type mice. We further demonstrated that the A␤ oligomer-induced sphingomyelinase activation was suppressed and that phosphorylation of Akt/protein kinase B (PKB) was preserved in neuronal cells isolated from cPLA 2 Ϫ/Ϫ mice. Interestingly, expression of the A␤ precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA 2 Ϫ/Ϫ mice, but the relationship with the resistance of these mice to the A␤ oligomer toxicity requires further investigation. These results therefore show that cPLA 2 plays a key role in the A␤ oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Desbène

Malaplate-Armand

Youssef

et al. 2012

Neurobiology of Aging

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“…Furthermore, disruption of AMPAR trafficking by soluble amyloid beta (Aβ) oligomers is a major causative agent of synaptic dysfunction in AD 144 . More specifically, it has been reported that Aβ oligomers bind in close proximity to GluA2-containing complexes and AMPAR antagonists inhibit Aβ oligomer binding and synaptic loss, raising the possibility that Aβ may affect AMPAR trafficking by binding directly to the GluA2 protein complex 145 . Conversely, intracellular application of oligomerised Aβ causes an acute increase in AMPAR-mediated synaptic responses, which requires PKA phosphorylation of S845 in GluA1.…”

Section: Ampar Subunits and Diseasementioning

confidence: 99%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. PrefaceAMPARs are assemblies of four core subunits, GluA1-4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity, and in response to neuronal stress in disease. Recently, the subunit-dependence of AMPAR trafficking has been questioned leading to a reappraisal of the field. Here we review what is known, uncertain, conjectured and unknown about the roles of individual subunits and how they impact on AMPAR assembly, trafficking and function under normal and pathological conditions. IntroductionAMPA receptors (AMPARs) are a subtype of ionotropic glutamate receptors that are the 'work-horses' of fast excitatory neurotransmission in the CNS. Developmentallyand activity-regulated changes in the numbers and properties of AMPARs localized at the postsynaptic membrane are essential for excitatory synapse formation, stabilization, synaptic plasticity and neural circuit formation. Consequently, the logistics of the delivery, retention and removal of individual AMPARs with defined subunit compositions at specific synapses is highly complex. A typical cortical or hippocampal pyramidal neuron contains on the order of 10,000 synapses and the AMPARs at each synapse are independently and dynamically regulated in response to developmental cues, synaptic activity and environmental stresses. Furthermore, defects in the processes that control AMPAR assembly, trafficking and synaptic expression are intimately linked to psychiatric and neurological conditions, and also with cognitive decline in neurodegenerative diseases. Remarkable progress has been achieved in understanding how AMPAR trafficking, is orchestrated by a large array of AMPAR interacting proteins. These studies have established a set of hierarchical subunit-specific rules that control AMPAR trafficking under basal and activity-dependent conditions. Furthermore, there has been a growing appreciation that subunit composition can tune the properties of AMPARs to specific conditions. Nonetheless, how AMPARs comprising different subunits are differentially trafficked to control synaptic development, stabilisation and plasticity is a key unanswered question. Here, we provide an overview of the current state of knowledge of subunit-specific AMPAR trafficking and outline what we believe to be the key unresolved questions in the field. 2 Subunit-specific traffickingMost AMPARs are heterotetrameric assemblies of combinations of the subunits GluA1, GluA2, GluA3 and GluA4. AMPARs are expressed in both neurons and glia throughout the CNS 1 and have a turnover time of between 10 hours and 2 days depending on the type of neuron and developmental stage 2,3 . Each subunit has an identical membrane topology and c...

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“…Accordingly, several reports have shown that oA␤ inhibited LTP and facilitated LTD (5,6,(17)(18)(19), probably by inducing internalization of NMDAR and AMPAR (13,16,17). Although changes in [Ca 2ϩ ] i are important to trigger LTP or LTD (7), the effect of oA␤ on the intracellular calcium levels and its contribution to the deregulation of LTP and LTD are still a controversial issue (20).…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

“…Increasing the extrasynaptic pool of AMPAR has been proposed to be a critical event for the establishment of LTP (12). Recent reports have shown that oA␤ could alter AMPAR endocytosis by modulating downstream kinases and phosphatases (13)(14)(15).…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

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

Miñano-Molina

España

Martín

et al. 2011

Journal of Biological Chemistry

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␤-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

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Inhibition of Calcineurin-mediated Endocytosis and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Prevents Amyloid β Oligomer-induced Synaptic Disruption

Cited by 173 publications

References 84 publications

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Synaptic AMPA receptor composition in development, plasticity and disease

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

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