Soluble A Oligomers Inhibit Long-Term Potentiation through a Mechanism Involving Excessive Activation of Extrasynaptic NR2B-Containing NMDA Receptors

Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2011; 31(18):6627-38. DOI: 10.1523/JNEUROSCI.0203-11.2011
Source: PubMed


In Alzheimer's disease (AD), dementia severity correlates strongly with decreased synapse density in hippocampus and cortex. Numerous studies report that hippocampal long-term potentiation (LTP) can be inhibited by soluble oligomers of amyloid β-protein (Aβ), but the synaptic elements that mediate this effect remain unclear. We examined field EPSPs and whole-cell recordings in wild-type mouse hippocampal slices. Soluble Aβ oligomers from three distinct sources (cultured cells, AD cortex, or synthetic peptide) inhibited LTP, and this was prevented by the selective NR2B inhibitors ifenprodil and Ro 25-6981. Soluble Aβ enhanced NR2B-mediated NMDA currents and extrasynaptic responses; these effects were mimicked by the glutamate reuptake inhibitor dl-threo-β-benzyloxyaspartic acid. Downstream, an Aβ-mediated rise in p38 mitogen-activated protein kinase (MAPK) activation was followed by downregulation of cAMP response element-binding protein, and LTP impairment was prevented by inhibitors of p38 MAPK or calpain. Thus, soluble Aβ oligomers at low nanomolar levels present in AD brain increase activation of extrasynaptic NR2B-containing receptors, thereby impairing synaptic plasticity.

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Available from: Shaomin Li
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    • "Encouraging results have already been obtained using activin A as a neuroprotective agent in a rat lesion model of HD (Hughes et al., 1999). Recent work demonstrated that overexpression of mutant huntingtin induces phosphorylation of the NR2B subunit at tyrosine residue 1472 in vitro (Song et al., 2003), sensitizes NMDA receptors, and induces excitotoxicity in vivo (Zeron et al., 2002), indicating that cell loss in HD (and perhaps also in other neurodegenerative diseases; Li et al., 2011) may result from a shift in the balance of NMDA receptor signaling from the survival-promoting synaptic NMDA receptor toward extrasynaptic NMDA receptors that initiate cell death pathways (Hardingham et al., 2002; Hardingham and Bading, 2010; Parsons and Raymond, 2014). By showing that BDNF/ inhba signaling regulates and restores the balance in NMDA receptor signaling by affecting phosphorylation of the NR2B subunit at tyrosine residue 1472 and reducing the toxic, extrasynaptic NMDA-receptor-induced calcium influx, our data causally link these findings by delivering an explanation as to how activin A may rescue BDNF-deficient neurons from neuronal dysfunction and cell death associated with, or caused by, an imbalance in extrasynaptic versus synaptic NMDA receptor signaling. "
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    ABSTRACT: The health of neurons is critically dependent on the relative signaling intensities of survival-promoting synaptic and death-inducing extrasynaptic NMDA receptors. Here, we show that BDNF is a regulator of this balance and promotes neuroprotection by reducing toxic NMDA receptor signaling. BDNF acts by initiating synaptic NMDA-receptor/nuclear-calcium-driven adaptogenomics, leading to increased expression of inhibin β-A (inhba). Inhibin β-A (its homodimer is known as activin A) in turn reduces neurotoxic extrasynaptic NMDA-receptor-mediated calcium influx, thereby shielding neurons against mitochondrial dysfunction, a major cause of excitotoxicity. Thus, BDNF induces acquired neuroprotection by enhancing synaptic activity and lowering extrasynaptic NMDA receptor death signaling through a nuclear calcium-inhibin β-A pathway. This process, which confers protection against ischemic brain damage in a mouse stroke model, may be compromised in Huntington's disease, Alzheimer's disease, or aging-related neurodegenerative conditions that are associated with reduced BDNF levels and/or enhanced extrasynaptic NMDA receptor signaling. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Cell Reports
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    • "When LTP was induced by 1–3 bouts of TBS under physiological recording conditions, there was no difference between wt and PS2APP mice (Fig. 1B). Since many previous studies have shown that GluN2B-NMDAR antagonists rescue impairment of LTP caused by acute application of Aβ (Li et al., 2011; Olsen and Sheng, 2012; Rammes et al., 2011; Ronicke et al., 2011), we determined whether the LTP in PS2APP mice could be altered by the selective GluN2B antagonist Ro25. To our surprise, while Ro25 did not affect wt LTP, a significant reduction in LTP was seen in slices from PS2APP mice in the presence of Ro25 (Fig. 1C, D, F). "
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    ABSTRACT: GluN2B subunit containing NMDARs (GluN2B-NMDARs) mediate pathophysiological effects of acutely applied Amyloid Beta (Aβ), including impaired long-term potentiation (LTP). However, in transgenic Alzheimer's disease (AD) mouse models which feature gradual Aβ accumulation, the function of GluN2B-NMDARs and their contribution to synaptic plasticity are unknown. Therefore, we examined the role of GluN2B-NMDARs in synaptic function and plasticity in the hippocampus of PS2APP transgenic mice. Although LTP induced by theta burst stimulation (TBS) was normal in PS2APP mice, it was significantly reduced by the selective GluN2B-NMDAR antagonist Ro25-6981 (Ro25) in PS2APP mice, but not wild type (wt) mice. While NMDARs activated by single synaptic stimuli were not blocked by Ro25, NMDARs recruited during burst stimulation showed larger blockade by Ro25 in PS2APP mice. Thus, the unusual dependence of LTP on GluN2B-NMDARs in PS2APP mice suggests that non-synaptic GluN2B-NMDARs are activated by glutamate that spills out of synaptic cleft during the burst stimulation used to induce LTP. While long-term depression (LTD) was normal in PS2APP mice, and Ro25 had no impact on LTD in wt mice, Ro25 impaired LTD in PS2APP mice, again demonstrating aberrant GluN2B-NMDAR function during plasticity. Together these results demonstrate altered GluN2B-NMDAR function in a model of early AD pathology that has implications for the therapeutic targeting of NMDARs in AD. Copyright © 2014. Published by Elsevier Inc.
    Full-text · Article · Dec 2014 · Neurobiology of Disease
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    • "Several studies have reported that Aβ oligomers negatively modulate synaptic plasticity (Walsh et al., 2002; Cleary et al., 2005; Li et al., 2011; Ferreira and Klein, 2011). Previously, we showed that Aβ oligomers also reduce synaptic efficacy and impair hippocampal synaptic transmission, mainly by decreasing the NMDA and AMPA receptor currents , which is potentially caused by a reduction in the levels of PSD-95 and the number of synaptic contacts (Cerpa et al., 2010). "
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    ABSTRACT: Amyloid-β (Aβ) oligomers are a key factor in Alzheimer's disease (AD)-associated synaptic dysfunction. Aβ oligomers block the induction of hippocampal long-term potentiation (LTP) in rodents. The activation of Wnt signaling prevents Aβ oligomer-induced neurotoxic effects. The compound WASP-1 (Wnt-activating small molecule potentiator-1), has been described as a synergist of the ligand Wnt-3a, enhancing the activation of Wnt/β-catenin signaling. Herein, we report that WASP-1 administration successfully rescued Aβ-induced synaptic impairments both in vitro and in vivo. The activation of canonical Wnt/β-catenin signaling by WASP-1 increased synaptic transmission and rescued hippocampal LTP impairments induced by Aβ oligomers. Additionally, intra-hippocampal administration of WASP-1 to the double transgenic APPswe/PS1dE9 mouse model of AD prevented synaptic protein loss and reduced tau phosphorylation levels. Moreover, we found that WASP-1 blocked Aβ aggregation in vitro and reduced pathological tau phosphorylation in vivo. These results indicate that targeting canonical Wnt signaling with WASP-1 could have value for treating AD. Copyright © 2014. Published by Elsevier Inc.
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