Metabotropic NMDA receptor function is required for -amyloid-induced synaptic depression
Center for Neural Circuits and Behavior, Departments of Neuroscience and Biology, University of California at San Diego, La Jolla, CA 92093.Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2013; 110(10):4033-8. DOI: 10.1073/pnas.1219605110
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.
Full-text previewDOI: · Available from: pnas.org
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.
[Show abstract] [Hide abstract]
- "Interestingly, subsequent research into the properties of Ab has revealed that excessive levels of Ab inhibit activity-dependent synaptic plasticity, the basis for learning and memory (Koffie et al., 2011; LaFerla et al., 2007). For example, infusion of Ab in rats transiently impairs cognitive function (Cleary et al., 2005), and acute neuronal overproduction of Ab blocks synaptic plasticity (Kessels et al., 2013; Wei et al., 2010). These unique synaptotoxic properties, together with its accumulation in both familial and sporadic AD, established Ab as a key player in AD. "
ABSTRACT: Neuronal activity directly promotes the production and secretion of amyloid β (Aβ). Interestingly, neuronal hyperactivity can be observed in presymptomatic stages of both sporadic and familial Alzheimer's disease (AD) and in several AD mouse models. In this review, we will highlight the recent evidence for neuronal hyperactivity before or during the onset of cognitive defects in mild cognitive impairment. Furthermore, we review specific molecular mechanisms through which neuronal hyperactivity affects Aβ production and degradation. With these data, we will provide more insight into the 2-faced nature of neuronal hyperactivity: does enhanced neuronal activity during the presymptomatic stages of AD provide protection against the earliest disease processes or is it a pathogenic contributor to AD? Copyright © 2014 Elsevier Inc. All rights reserved.
[Show abstract] [Hide abstract]
- "In the present study we demonstrate changes in Src-dependent signaling pathways involving modified GluN2B subunit and Dab1 phosphorylation, and actin cytoskeleton polymerization in post-synaptic sites in the 3xTg-AD mice model of AD. Direct activation of NMDARs by Aβ was previously described in AD (Texido et al., 2011; Costa et al., 2012; Kessels et al., 2013). We previously demonstrated that Aβ 1–42 immediately disturbs intracellular Ca 2+ homeostasis (Ferreira et al., 2012), namely through ER stress (Costa et al., 2012), and causes microtubule deregulation (Mota et al., 2012) by interacting with GluN2B-containing NMDARs, as observed in cortical and hippocampal neurons, revealing an important role of this NMDAR subunit. "
ABSTRACT: Early cognitive deficits in Alzheimer's disease (AD) have been related to deregulation of N-methyl-D-aspartate receptors (NMDARs) and synaptic dysfunction in response to amyloid-beta peptide. NMDARs anchorage to post-synaptic membrane depends in part on Src kinase, which is also implicated in NMDAR activation and actin cytoskeleton stabilization, two processes relevant for normal synaptic function. In this study we analysed the changes in GluN2B subunit phosphorylation and the levels of proteins involved in Src related signaling pathways linking the Tyr kinase to actin cytoskeleton polymerization, namely reelin, disabled-1 (Dab1) and cortactin, in hippocampal and cortical homogenates obtained from the triple transgenic mouse model of AD (3xTg-AD) that shows progression of pathology as a function of age versus age-matched wild-type mice. Moreover, we evaluated regional post-synaptic actin polymerization using phalloidin labelling in hippocampal slices. Young (3month-old) 3xTg-AD mice male hippocampus exhibited decreased GluN2B Tyr1472 phosphorylation and reduced Src activity. In the cortex, decreased Src activity correlated with reduced levels of reelin and Dab1, implicating changes in the reelin pathway. We also observed diminished phosphorylated Dab1 and cortactin protein levels in hippocampus and cortex of young 3xTg-AD male mice. Concordantly with the recognized role of these proteins in actin stabilization, we detected a significant decrease in post-synaptic F-actin in 3month-old 3xTg-AD male CA1 and CA3 hippocampal regions. These data suggest deregulated Src-dependent signaling pathways involving GluN2B-composed NMDARs and post-synaptic actin cytoskeleton depolymerization in the hippocampus in early stages of AD.
[Show abstract] [Hide abstract]
- "The editing process of GluA2 pre-mRNAs results in the substitution of a codon for glutamine (CAG) with a codon for arginine (CGG) at the so-called Q/R site. This post-transcriptional change of GluA2 transcripts confers to AMPARs impermeability to Ca 2+ and other divalents (Kawahara et al., 2004). Incomplete editing has been shown to occur in neuropathological conditions and we have therefore evaluated the process in our preclinical AD model. "
ABSTRACT: GluA1, GluA2, GluA3, and GluA4 are the constitutive subunits of AMPA receptors (AMPARs), the major mediators of fast excitatory transmission in the mammalian central nervous system. Most AMPARs are Ca2+-impermeable because of the presence of the GluA2 subunit. GluA2 mRNA undergoes an editing process that results in a Q to R substitution, a key factor in the regulation of AMPAR Ca2+-permeability. AMPARs lacking GluA2 or containing the unedited subunit are permeable to Ca2+ and Zn2+. The phenomenon physiologically modulates synaptic plasticity while, in pathologic conditions, leads to increased vulnerability to excitotoxic neuronal death. Given the importance of these subunits, we have therefore evaluated possible associations between changes in expression levels of AMPAR subunits and development of cognitive deficits in 3xTg-AD mice, a widely investigated transgenic mouse model of Alzheimer’s disease. With qRT-PCR, we assayed hippocampal mRNA expression levels of GluA1-4 subunits occurring in young [3 months of age (m.o.a.)] and old (12 m.o.a) Tg-AD mice and made comparisons with levels found in age-matched wild type (WT) mice. Efficiency of GluA2 RNA editing was also analyzed. All animals were cognitively tested for short- and long-term spatial memory with the Morris Water Maze (MWM) navigation task. 3xTg-AD mice showed age-dependent decreases of mRNA levels for all the AMPAR subunits, with the exception of GluA2. Editing remained fully efficient with aging in 3xTg-AD and WT mice. A one-to-one correlation analysis between MWM performances and GluA1-4 mRNA expression profiles showed negative correlations between GluA2 levels and MWM performances in young 3xTg-AD mice. On the contrary, positive correlations between GluA2 mRNA and MWM performances were found in young WT mice. Our data suggest that increases of AMPARs that contain GluA1, GluA3, and GluA4 subunits may help in maintaining cognition in pre-symptomatic 3xTg-AD mice.