Amyloid β peptide oligomers directly activate NMDA receptors

Texidó, Laura; Martı́n-Satué, Mireia; Alberdi, Elena; Solsona, Carles; Matute, Carlos

doi:10.1016/j.ceca.2011.02.001

Cited by 190 publications

(133 citation statements)

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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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“…An increased production of Aβ leads to synaptic depression, a loss of spines, and a reduced capacity for synaptic plasticity (6)(7)(8)(9)(10)(11)(12)(13)(14). However, the signaling pathways used by Aβ to cause its synapto-toxic effects are poorly understood.…”

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confidence: 99%

Metabotropic NMDA receptor function is required for β-amyloid–induced synaptic depression

Kessels

Nabavi

Malinow

2013

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

158

145

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The mechanisms by which β-amyloid (Aβ), a peptide fragment believed to contribute to Alzheimer's disease, leads to synaptic deficits are not known. Here we find that elevated oligomeric Aβ requires ion flux-independent function of NMDA receptors (NMDARs) to produce synaptic depression. Aβ activates this metabotropic NMDAR function on GluN2B-containing NMDARs but not on those containing GluN2A. Furthermore, oligomeric Aβ leads to a selective loss of synaptic GluN2B responses, effecting a switch in subunit composition from GluN2B to GluN2A, a process normally observed during development. Our results suggest that conformational changes of the NMDAR, and not ion flow through its channel, are required for Aβ to produce synaptic depression and a switch in NMDAR composition. This Aβ-induced signaling mediated by alterations in GluN2B conformation may be a target for therapeutic intervention of Alzheimer's disease.synapse | ion-flow independent | amyloid-beta | NR2A | NR2B

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“…A number of studies also indicate that there are further sites of calcium entry that are modulated by Aβ. For example, Texidó et al (2011) show that Aβ oligomers modulate NMDA receptors recombinantly expressed in X. laevis oocytes. Such down-regulation of the NMDA receptor current also reduces calcium influx into the cell, which was demonstrated in neurons by Shankar et al (2007).…”

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confidence: 99%

Calcium channel blockers and dementia

Nimmrich

Eckert

2013

British J Pharmacology

128

102

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Degenerative dementia is mainly caused by Alzheimer's disease and/or cerebrovascular abnormalities. Disturbance of the intracellular calcium homeostasis is central to the pathophysiology of neurodegeneration. In Alzheimer's disease, enhanced calcium load may be brought about by extracellular accumulation of amyloid-β. Recent studies suggest that soluble forms facilitate influx through calcium-conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration. Calcium channel blockade attenuates amyloid-β-induced neuronal decline in vitro and is neuroprotective in animal models. Vascular dementia, on the other hand, is caused by cerebral hypoperfusion and may benefit from calcium channel blockade due to relaxation of the cerebral vasculature. Several calcium channel blockers have been tested in clinical trials of dementia and the outcome is heterogeneous. Nimodipine as well as nilvadipine prevent cognitive decline in some trials, whereas other calcium channel blockers failed. In trials with a positive outcome, BP reduction did not seem to play a role in preventing dementia, indicating a direct protecting effect on neurons. An optimization of calcium channel blockers for the treatment of dementia may involve an increase of selectivity for presynaptic calcium channels and an improvement of the affinity to the inactivated state. Novel low molecular weight compounds suitable for proof-of-concept studies are now available. AbbreviationsAβ, amyloid-β; AD, Alzheimer's disease; APP, amyloid precursor protein; LTP, long-term potentiation; VaD, vascular dementia; VGCC, voltage-gated calcium channel IntroductionDementia affects 7% of the population over the age of 65, and then progressively increases with age Rocca et al., 1991). Alzheimer's disease (AD) is the leading cause of dementia, followed by vascular dementia (VaD). AD is characterized by three neuropathological hallmarks: extracellular aggregates of amyloid-β (Aβ) peptide (amyloid plaques), neurofibrillary tangles and synaptic loss (Bell and Cuello, 2006). According to the amyloid cascade hypothesis, overproduction of the hydrophobic peptide Aβ 1-42 is the basis for AD pathology (Hardy and Higgins, 1992).Aggregation of Aβ 1-42 is thought to occur in several steps via fibrils, which are finally deposited as amyloid plaques. It was suggested that an alternative pathway leads to the generation of stable oligomeric aggregates, Aβ oligomers (Gellermann et al., 2008;Yu et al., 2009b), which are considered to mediate the toxic Aβ effects (Hardy and Selkoe, 2002). Different forms of Aβ oligomers can be generated synthetically (e.g. Stine et al., 2003; Barghorn et al., 2005) or are harvested from cell lines (Walsh et al., 2002). These preparations were tested in vitro and in animal models, and the results lead to the generally accepted view that Aβ oligomers specifically disturb synaptic function . Constant impairment of neurotransmission leads to a retraction of synapses, which is then evident in the autopsy of AD brains (for a review, see Nimmrich a...

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Amyloid β peptide oligomers directly activate NMDA receptors

Cited by 190 publications

References 35 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

Metabotropic NMDA receptor function is required for β-amyloid–induced synaptic depression

Calcium channel blockers and dementia

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