NMDA Receptor Activation Inhibits α-Secretase and Promotes Neuronal Amyloid-β Production

Lesné, Sylvain; Ali, Carine; Gabriel, C.; Croci, Nicole; MacKenzie, Eric T.; Glabe, Charles G.; Plotkine, Michel; Marchand-Verrecchia, Catherine; Vivien, Denis; Buisson, Alain

doi:10.1523/jneurosci.0849-05.2005

Cited by 178 publications

(134 citation statements)

References 61 publications

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“…Early studies showed that electrical depolarization increases the release of soluble APP-a in rat hippocampal brain slices (Nitsch et al 1993), and it appears that these effects are mediated by activation of muscarinic M1 acetylcholine receptors which leads to parallel decreases in Ab levels (Beach et al 2001;Hock et al 2003). On the other hand, specific stimulation of NMDA receptors up-regulates APP, inhibits a-secretase activity, and promotes Ab production (Lesne et al 2005).…”

Section: Activity-dependent App Processingmentioning

confidence: 99%

Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

893

892

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Accumulations of insoluble deposits of amyloid b-peptide are major pathological hallmarks of Alzheimer disease. Amyloid b-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the b-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. b-and g-secretase liberate by sequential cleavage the neurotoxic amyloid b-peptide, whereas a-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid b-peptide generation and therefore disease onset and progression.

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Section: Activity-dependent App Processingmentioning

confidence: 99%

Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

893

892

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“…Importantly, using antibodies against the N-terminal component of GluN1 or GluN2B subunits, our data supports that Aβ oligomers are able to bind NMDARs extracellularly (Costa et al, 2012). On the other hand, NMDARs activation (Lesne et al, 2005), and more particularly extrasynaptic activation (Bordji et al, 2010), triggers increased production and secretion of Aβ, which is preceded by a shift from APP695 to Kunitz protease inhibitory domain (KPI) containing APPs, isoforms exhibiting a high amyloidogenic potential, followed by a shift from α-secretase to β-secretase-mediated APP processing, largely suggesting a circuit in which Aβ facilitates NMDARs activation, which in turn promotes Aβ production.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…Furthermore, NMDARs activation, particularly extrasynaptic NMDARs (Bordji et al, 2010), promote neuronal Aβ secretion (Lesne et al, 2005). Thus, the use of treatments targeting NMDARs seem to be a promising therapeutic option to counteract AD progression.…”

Section: Nmdars As Targets For Therapeutic Intervention In Admentioning

confidence: 99%

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

Mota¹,

Ferreira²,

Rego³

2014

Neuropharmacology

170

100

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Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly.Alterations capable of causing brain circuitry dysfunctions in AD may take several years to develop. Oligomeric amyloid-beta peptide (Aβ) plays a complex role in the molecular events that lead to progressive loss of function and eventually to neurodegeneration in this devastating disease. Moreover, N-methyl-D-aspartate (NMDA) receptors (NMDARs) activation has been recently implicated in AD-related synaptic dysfunction. Thus, in this review we focus on glutamatergic neurotransmission impairment and the changes in NMDAR regulation in AD, following the description on the role and location of NMDARs at pre-and post-synaptic sites under physiological conditions. In addition, considering that there is currently no effective ways to cure AD or stop its progression, we further discuss the relevance of NMDARs antagonists to prevent AD symptomatology. This review posits additional information on the role played by Aβ in AD and the importance of targeting the tripartite glutamatergic synapse in early asymptomatic and possible reversible stages of the disease through preventive and/or disease-modifying therapeutic strategies.

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“…We initially demonstrated that a prolonged stimulation of cortical neuron cultures with a sublethal concentration of NMDA increased the production and secretion of A β (Lesn é et al, 2005 ). This effect was preceded by an important modifi cation of neuronal APP expression pattern with the expression of an APP isoform which is normally absent in neurons: the Kunitz protease inhibitor (KPI) domain containing APP (KPI-APP).…”

Section: Nmdar Activation and Neuronal A β Synthesismentioning

confidence: 99%

“…Moreover, excessive NMDAR activity was shown to contribute importantly to the etiology of many acute or chronic neurodegenerative disorders such as stroke, Hungtinton ' s disease, HIV-associated dementia and AD (Lipton and Rosenberg , 1994 ;Lancelot and Beal , 1998 ). Several studies reported a direct link between NMDAR overactivation on the one hand, and APP processing and neuronal A β secretion on the other hand, even if the conclusions could be somewhat different (Lesn é et al, 2005 ;Marcello et al , 2007 ;Hoey et al , 2009 ). It was further demonstrated that the cellular location of NMDARs is a key parameter controlling their effect on neuronal viability.…”

Section: Introductionmentioning

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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NMDA Receptor Activation Inhibits α-Secretase and Promotes Neuronal Amyloid-β Production

Cited by 178 publications

References 61 publications

Trafficking and Proteolytic Processing of APP

Trafficking and Proteolytic Processing of APP

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

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

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