GluN2B subunit-containing NMDA receptor antagonists prevent Aβ-mediated synaptic plasticity disruption in vivo

Hu, Neng‐Wei; Klyubin, Igor; Anwyl, Roger; Rowan, Michael J.

doi:10.1073/pnas.0908083106

Cited by 150 publications

(115 citation statements)

References 71 publications

(73 reference statements)

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“…Moreover, we found strong evidence that the inhibition of NMDAR-dependent LTP by Ab is prevented by selective block of GluN2B subunit-containing NMDARs in vivo [11], which was confirmed in vitro [12][13][14]. However, not all NMDAR-dependent LTP is susceptible to inhibition by Ab, and Ab can facilitate NMDAR-independent long-term depression [11,12,15]. In order to compare the effect of Ab on NMDAR-dependent and -independent forms of LTP in vivo, we have used two different high-frequency conditioning stimulation (HFS) protocols.…”

Section: Ab-mediated Disruption Of Nmdardependent and -Independent Fomentioning

confidence: 75%

Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aβ in vivo

Klyubin

Ondrejčák²,

Hayes³

et al. 2014

Phil. Trans. R. Soc. B

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Many endogenous factors influence the time course and extent of the detrimental effects of amyloid β-protein (Aβ) on synaptic function. Here, we assessed the impact of varying endogenous glutamatergic and cholinergic transmission by pharmacological means on the disruption of plasticity at hippocampal CA3-to-CA1 synapses in the anaesthetized rat. NMDA receptors (NMDARs) are considered critical in mediating Aβ-induced inhibition of long-term potentiation (LTP). However, intracerebroventricular injection of Aβ 1–42 inhibited not only NMDAR-dependent LTP but also voltage-activated Ca 2+ -dependent LTP induced by strong conditioning stimulation during NMDAR blockade. On the other hand, another form of NMDAR-independent synaptic plasticity, endogenous acetylcholine-induced muscarinic receptor-dependent long-term enhancement, was not hindered by Aβ 1–42 . Interestingly, augmenting endogenous acetylcholine activation of nicotinic receptors prior to the injection of Aβ 1–42 prevented the inhibition of NMDAR-dependent LTP, whereas the same intervention when introduced after the infusion of Aβ was ineffective. We also examined the duration of action of Aβ, including water soluble Aβ from Alzheimer's disease (AD) brain. Remarkably, the inhibition of LTP induction caused by a single injection of sodium dodecyl sulfate-stable Aβ dimer-containing AD brain extract persisted for at least a week. These findings highlight the need to increase our understanding of non-NMDAR mechanisms and of developing novel means of overcoming, rather than just preventing, the deleterious synaptic actions of Aβ.

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Section: Ab-mediated Disruption Of Nmdardependent and -Independent Fomentioning

confidence: 75%

Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aβ in vivo

Klyubin

Ondrejčák²,

Hayes³

et al. 2014

Phil. Trans. R. Soc. B

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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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“…Moreover, in rats co-injected with Aβ and ifenprodil prevented Aβ-mediated inhibition of plasticity (Hu et al, 2009). …”

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

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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GluN2B subunit-containing NMDA receptor antagonists prevent Aβ-mediated synaptic plasticity disruption in vivo

Cited by 150 publications

References 71 publications

Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aβ in vivo

Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aβ in vivo

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

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

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