Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses

Papadia, Sofia; Soriano, Francesc X.; Léveillé, Frédéric; Martel, Marc-André; Dakin, Kelly A.; Hansen, Henrik H.; Kaindl, Angela M.; Sifringer, Marco; Fowler, Jill H.; Stefovska, Vanya; McKenzie, Grahame J.; Craigon, Marie; Corriveau, Roderick A.; Ghazal, Peter; Horsburgh, Karen; Yankner, Bruce A.; Wyllie, David J. A.; Ikonomidou, Chrysanthy; Hardingham, Giles E.

doi:10.1038/nn2071

Cited by 468 publications

(541 citation statements)

References 51 publications

(86 reference statements)

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“…This preparation allows rapid access of exogenous Aβ and applied drugs to neural tissue and also simultaneous recording of eNMDARs and sNMDARs with a single patch electrode. In hippocampal autaptic cultures, we found that picomolar naturally occurring Aβ-soluble oligomers, nanomolar oligomeric Aβ 1-42 (but not monomeric), or low-micromolar Aβ [25][26][27][28][29][30][31][32][33][34][35] (but not Aβ ) induced a tonic inward current within tens of seconds of application in ∼55% of neurons (Fig. 2 A-G; n = 90).…”

Section: Aβ Increases Extrasynaptic Glutamatergic Currents But Decreasesmentioning

confidence: 95%

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

Talantova

Sanz-Blasco

Zhang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

502

524

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Significance Communication between nerve cells occurs at specialized cellular structures known as synapses. Loss of synaptic function is associated with cognitive decline in Alzheimer’s disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here we describe a pathway for synaptic damage whereby amyloid-β 1–42 peptide (Aβ 1–42 ) releases, via stimulation of α7 nicotinic receptors, excessive amounts of glutamate from astrocytes, in turn activating extrasynaptic NMDA-type glutamate receptors (eNMDARs) to mediate synaptic damage. The Food and Drug Administration-approved drug memantine offers some beneficial effect, but the improved eNMDAR antagonist NitroMemantine completely ameliorates Aβ-induced synaptic loss, providing hope for disease-modifying intervention in AD.

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Section: Aβ Increases Extrasynaptic Glutamatergic Currents But Decreasesmentioning

confidence: 95%

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

Talantova

Sanz-Blasco

Zhang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

502

524

View full text Add to dashboard Cite

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“…On the other hand, activation of synaptic NMDAR is not coupled to hippocampal neuron damage (Hardingham et al, 2002), but rather promotes resistance to oxidative insults and prevents accumulation of reactive oxygen species in cortical neurons (Papadia et al, 2008) (Fig. 1).…”

Section: Role Of Glutamatementioning

confidence: 99%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

114

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A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

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“…In fact, different independent papers reported that, unlike other classical NMDAR antagonists (e.g., MK801, AP5), memantine preferentially blocks extrasynaptic over synaptic NMDAR currents in neurons Xia et al , 2010 ). The importance of maintaining normal synaptic NMDA signaling has been interestingly underlined by Papadia et al who showed that synaptic NMDA activity is necessary to boost intrinsic antioxidant defenses (Papadia et al , 2008 ).…”

Section: Targeting Extrasynaptic Nmdars To Lower a β Peptide: Interesmentioning

confidence: 99%

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

Bordji

Becerril-Ortega

2011

Revneuro

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A direct relationship has been established between synaptic activity and amyloid-β secretion. Dysregulation of neuronal calcium homeostasis was shown to increase production of amyloid-β , contributing to the initiation of Alzheimer ' s disease. Among the different routes of Ca 2 + entry, N -methyld -aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are especially involved in this process because of their ability to gate high levels of Ca 2 + infl ux. These receptors have been extensively studied for their crucial roles in synaptic plasticity that underlies learning and memory but also in neurotoxicity occurring during acute brain injuries and neurodegenerative diseases. For one decade, several studies provided evidence that NMDA receptor activation could have distinct consequences on neuronal fate, depending on their location. Synaptic NMDA receptor activation is neuroprotective, whereas extrasynaptic NMDA receptors trigger neuronal death and/or neurodegenerative processes. Recent data suggest that chronic activation of extrasynaptic NMDA receptors leads to a sustained neuronal amyloid-β release and could be involved in the pathogenesis of Alzheimer ' s disease. Thus, as for other neurological diseases, therapeutic targeting of extrasynaptic NMDA receptors could be a promising strategy. Following this concept, memantine, unlike other NMDA receptor antagonists was shown, to preferentially target the extrasynaptic NMDA receptor signaling pathways, while relatively sparing normal synaptic activity. This molecular mechanism could therefore explain why memantine is, to date, the only clinically approved NMDA receptor antagonist for the treatment of dementia.

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Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses

Cited by 468 publications

References 51 publications

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

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