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Post-synaptic scaffolding protein interactions with glutamate receptors insynaptic dysfunction and Alzheimer’s disease

Dustin T. Proctor a, Elizabeth J. Coulson b, Peter R. Dodd a,*a School of Chemistry and Molecular Biosciences, Molecular Biosciences Building #76, Coopers Road, St Lucia campus, University of Queensland, Brisbane 4072, Australiab Brain Institute, University of Queensland, Brisbane, Australia

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 510

2. PSD-MAGUK functions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 510

2.1. Glutamate receptor–PSD-MAGUK interactions in LTP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511

2.2. PSD-MAGUK protein expression in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511

2.3. NMDA receptor changes in AD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511

2.4. AMPA receptor changes in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512

2.5. Ab-evoked LTP changes in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513

2.5.1. Ab induced LTP deficits in AD via altered NMDA receptor-PSD-MAGUK interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513

2.5.2. Ab induced LTP deficits in AD via altered AMPA receptor–PSD-MAGUK interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513

2.6. PSD-MAGUK-dependent glutamate signaling changes in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514

2.6.1. CaMKII . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514

2.6.2. Phosphatidylinositol 3-kinase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514

2.7. PSD-MAGUK–glutamate receptor interactions in excitotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516

2.7.1. NR2B–PSD-MAGUK-induced excitotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516

2.7.2. nNOS–PSD-MAGUK-induced excitotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516

2.8. PSD-MAGUK inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517

Progress in Neurobiology 93 (2011) 509–521

A R T I C L E I N F O

Article history:

Received 13 August 2010

Received in revised form 18 February 2011

Accepted 24 February 2011

Available online xxx

Keywords:

Maguk

PSD-95

SAP-102

NMDA

Excitotoxicity

Trafficking

A B S T R A C T

Alzheimer’s disease (AD) is characterized clinically by an insidious decline in cognition. Much attention

has been focused on proposed pathogenic mechanisms that relate Ab plaque and neurofibrillary tangle

pathology to cognitive symptoms, but compelling evidence now identifies early synaptic loss and

dysfunction, which precede plaque and tangle formation, as the more probable initiators of cognitive

impairment. Glutamate-mediated transmission is severely altered in AD. Glutamate receptor expression

is most markedly altered in regions of the AD brain that show the greatest pathological changes.

Signaling via glutamate receptors controls synaptic strength and plasticity, and changes in these

parameters are likely to contribute to memory and cognitive deficits in AD. Glutamate receptor

expression and activity are modulated by interactions with post-synaptic scaffolding proteins that

augment the strength and direction of signal cascades initiated by glutamate receptor activity. Scaffold

proteins offer promising targets for more focused and effective drug therapy. In consequence, interest is

developing into the roles these proteins play in neurological disease. In this review we discuss

disruptions to excitatory neurotransmission at the level of glutamate receptor–post-synaptic scaffolding

protein interactions that may contribute to synaptic dysfunction in AD.

� 2011 Elsevier Ltd. All rights reserved.

Abbreviations: Ab, amyloid-b; AD, Alzheimer’s disease; AKAP, A Kinase Anchoring Protein; AMPAa, -amino-3-hydroxy-5-methyl-isoxazole-4-propionate; APP, amyloid

precursor protein; CaMKII, Ca2+/calmodulin-dependent kinase II; CREB, cAMP response element-binding protein; EAAT, excitatory amino acid transporter; FRAP, fluorescence

recovery after photobleaching; LTD, long-term depression; LTP, long-term potentiation; MAGUK, membrane-associated guanylate kinase; NFT, neurofibrillary tangle; NMDA,

N-methyl-D-aspartate; nNOS, neuronal nitric oxide synthase; PDZ, post-synaptic density protein–Drosophila disc large tumor suppressor–zonula occludens-1 protein; PI3K,

phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol-(4,5)-bisphosphate; PIP3, phosphatidylinositol-(3,4,5)-trisphosphate; PP2B, protein phosphatase 2B; PSD, post-

synaptic density; PTEN, phosphatase and tensin homologue deleted on chromosome 10; STEP, striatal-enriched phosphatase; TARP, transmembrane AMPA receptor

regulatory proteins.

* Corresponding author. Tel.: +61 7 3365 3364; fax: +61 7 3365 4699.

E-mail address: [email protected] (P.R. Dodd).

Contents lists available at ScienceDirect

Progress in Neurobiology

journa l homepage: www.e lsev ier .com/ locate /pneurobio

0301-0082/$ – see front matter � 2011 Elsevier Ltd. All rights reserved.

doi:10.1016/j.pneurobio.2011.02.002


3. Summary and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517

1. Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerativedisorder and the most common form of dementia, and has profounddetrimental effects on cognitive function. The neuropathologicalhallmarks that characterize AD comprise accumulations of extra-cellular amyloid-b (Ab) plaques and intraneuronal neurofibrillarytangles (NFTs) in vulnerable regions of the brain. Understandingpathogenic mechanisms in AD, and their relationships to neuropsy-chiatric symptoms, are major research priorities. There has been aprimary focus on the roles of Ab plaques and NFTs in diseaseprogression. However, Ab plaque load at autopsy does not conformto cognitive deficit ante mortem, and neuronal loss in affected brainregions does not reflect NFT abundance. Nerve-ending loss andsynaptic dysfunction are more-robust predictors of cognitiveimpairment (Kril et al., 2002; Nagy et al., 1995; Terry et al., 1991).

Deleterious changes in gene transcription and protein expres-sion that affect neurotransmission, plasticity, and hippocampallong-term potentiation (LTP) have been recorded in both humanand animal-model brains (Battaglia et al., 2007; Lin et al., 2003;Walsh et al., 2002; Williams et al., 2009). Glutamate-mediatedexcitatory transmission is disrupted in AD, and synaptic loss isparticularly severe for glutamatergic neurons (Francis, 2003;Hardy et al., 1987; Tannenberg et al., 2004). There is degenerationof neurons that express distinct subunit combinations of eitherionotropic glutamate N-methyl-D-aspartate (NMDA; Bi and Sze,2002; Hynd et al., 2004a,b) or a-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA; Armstrong et al., 1994) receptors:the possession of particular subunit combinations may determinethe degree of susceptibility of a post-synaptic neuron toglutamate-evoked excitotoxicity. NMDA and AMPA receptoractivity is necessary for hippocampal LTP, so receptor loss islikely to affect plasticity in the early stages of AD.

Glutamate receptor expression is regulated by interactions withthe post-synaptic density membrane-associated guanylate kinase(PSD-MAGUK) scaffolding proteins. PSD-MAGUKs indirectly regu-late AMPA receptor trafficking and expression and organize NMDAreceptors into multi-protein signaling complexes localized todendritic spines for receptor-mediated signaling (Elias and Nicoll,2007; Kim and Sheng, 2004). The neuronal expression of PSD-MAGUKs in the AD brain may influence the susceptibility ofneurons to glutamate-evoked degeneration: a loss of PSD-MAGUKsfrom the PSD, or altered interactions between receptors andscaffolding proteins, might follow changes in receptor subunitexpression. PSD-MAGUKs control synapse connectivity, morphol-ogy, and architecture, as well as dendritic growth and arborization– processes that are markedly altered in AD.

Reports of altered PSD-MAGUK expression in autopsied ADbrain tissue support this conjecture. We and others found regionand degeneration-specific changes/selective local differences inthe expression levels of two PSD-MAGUKs, PSD-95 and SAP-102, inAD brain (Gylys et al., 2004; Leuba et al., 2008a,b; Proctor et al.,2010). Altered PSD-MAGUK–glutamate-receptor interactions maybe of considerable biological importance in AD pathogenesis.

Glutamate-receptor-mediated excitotoxicity in AD has beenexamined in detail in recent reviews (Gasparini and Dityatev,2008; Parameshwaran et al., 2008; Walton and Dodd, 2007; Yamin,2009). The present paper focuses on the roles that PSD-MAGUKsplay in regulating glutamate receptors during synaptic plasticity,with particular emphasis on plastic changes in AD. We discuss

mechanisms that might change PSD-MAGUK protein levels in ADand how these changes could disrupt memory-related functionali-ties. We propose that PSD-MAGUK inhibitors and molecules thatinterfere with glutamate receptor–PSD-MAGUK interactions havepotential as novel candidate therapeutics for AD.

2. PSD-MAGUK functions

PSD-MAGUKs are PSD scaffolding proteins, of which four havebeen characterized in the CNS: PSD-95, PSD-93, SAP-97 and SAP-102. Their common structure comprises multiple protein–proteinbinding motifs, including a tandem array of PDZ-domain repeats.PSD-MAGUKs cluster and stabilize post-synaptic receptors onspines in close proximity to their intracellular signaling proteins,phosphatases, and kinases (Elias and Nicoll, 2007; Kim and Sheng,2004). This facilitates signal-transduction cascades initiated byreceptor stimulation, such as Ca2+/calmodulin-dependent kinase II(CaMKII) and phosphatidylinositol 3-kinase (PI3K) phosphoryla-tion. Their central function as scaffold proteins is demonstrated byPSD-MAGUK molecules being up to �10-fold more abundant thanglutamate receptors in the PSD (Feng and Zhang, 2009).

PSD-MAGUKs exhibit significant structural homology but differin developmental, subcellular, and regional expression in the brain.PSD-95 and PSD-93 are localized to active zones on post-synapticterminals, whereas SAP-102 is expressed peri-synaptically indendrites although it can also be found on axons and in thecytoplasm (Aoki et al., 2001; Kim and Sheng, 2004). SAP-97 islocated both pre-synaptically and post-synaptically in terminals ofthe forebrain and on unmyelinated axons (Muller et al., 1995).Splice variations, post-translational modifications such as palmi-toylation, and differences in affinity for specific receptors andsubtypes make it possible for PSD-MAGUKs to link activatedreceptors to distinct signaling pathways, and provide diversity inthe temporal expression of selective receptor subunit combina-tions in the brain (El-Husseini et al., 2000a; Schluter et al., 2006).

PSD-MAGUKs demonstrate their strongest interactions withNMDA receptors. Each PSD-MAGUK is able to bind each NR2subunit; however, PSD-93 and PSD-95 display their highestaffinities for the NR2A subunit while SAP-102 is predominantlyassociated with NR2B (Sans et al., 2000). The binding properties ofSAP-97 for NMDA receptors need to be clarified, but a single reportdemonstrated strong binding to post-synaptic NR2A subunits(Gardoni et al., 2003). The preferential selectivity of PSD-MAGUKproteins for NR2 subtypes underlies developmental differences inNR2A and NR2B expression, the predominant localization of NR2Asubunits to PSD-93- and PSD-95-enriched active sites, and NR2Band SAP-102 enrichment in extra-synaptic zones.

Studies on PSD-MAGUKs have been conducted for the most partin the rodent CNS, where in the mature brain, PSD-95 is the most-abundant member of the PSD-MAGUK family and probably themost biologically significant. Hence, PSD-95 is the most frequentlystudied and best-characterized PSD-MAGUK. Few studies havebeen devoted to PSD-MAGUK proteins in the human brain. Unlikein adult rodent cortex, SAP-102 is highly expressed in adult humanbrain along with the abundant PSD-95 (Proctor et al., 2010). Thismay be a regional phenomenon, because SAP-102 expression ishigh in mature rodent hippocampus (van Zundert et al., 2004).Nevertheless, significant SAP-102 expression was found in allhuman cortical areas studied (Proctor et al., 2010). More research isneeded into the levels and distribution of other scaffolding

D.T. Proctor et al. / Progress in Neurobiology 93 (2011) 509–521510


proteins in the aging human brain to determine whether theirfunctions differ from those in rodent brain.

PSD-MAGUK proteins bind cytoskeletal filaments and proteinsinvolved in synaptic connectivity, and control the architecture andmorphology of the synapse (Vessey and Karra, 2007). PSD-MAGUKexpression is crucial for synaptic strength and maturation, anddrives dendrite growth and spine formation. Direct and indirectbinding of PSD-MAGUKs augments the trafficking and stabilizationof AMPA receptors at active zones (Cai et al., 2006) as well as theirlateral diffusion along the synaptic membrane (Bats et al., 2007).This interaction is critical for LTP and plasticity.

2.1. Glutamate receptor–PSD-MAGUK interactions in LTP

LTP is arguably the cortical mechanism most pertinent tomemory formation and learning (Lisman et al., 2002; Nicoll andMalenka, 1999). LTP strengthens synapses during developmentand in activity-driven synaptogenesis in the adult. First describedin hippocampal CA1 pyramidal neurons, LTP follows Ca2+ influxthrough activated NMDA receptors, which induces short-termchanges in the activity of signaling enzymes and sustained, long-term changes in gene transcription, de novo protein synthesis, anddendritic spine generation and maturation (Kirkwood et al., 1993;Malenka and Bear, 2004; Nicoll and Malenka, 1999). LTP alsoincreases AMPA receptor currents by recruiting receptors to theactive site. AMPA receptor-dependent depolarization overcomesthe Mg2+ blockade of NMDA receptors; hence, increased synapticAMPA receptor activity and cell-surface expression enhance thetrans-synaptic excitatory response. Membrane insertion andremoval of AMPA receptors is the chief mechanism determiningthe strength of LTP (and long-term depression, LTD) changes in theCNS (Malenka and Bear, 2004).

Because PSD-MAGUKs regulate the number and compartmen-talization of both NMDA and AMPA receptors around the PSD, theirexpression influences LTP. The involvement of PSD-MAGUKs in LTPwas first investigated by El-Husseini et al. (2000b), who showed thatthe over-expression of PSD-95 protein in hippocampal neuronsdrove the maturation of glutamatergic synapses by increasing thenumber and activity of AMPA receptors, inducing dendrite spinegrowth and number, and restructuring the pre-synaptic terminal.PSD-95 is associated with experience-driven LTP in vivo. Animalshoused in experience-deprived conditions have impaired AMPA-mediated transmission. PSD-95 expression rescues this deficiency,but has no effect on normal AMPA currents in non-deprived animals(Ehrlich and Malinow, 2004). Consistent with these findings, PSD-95knockout mice show reduced AMPA-mediated transmission (Beıqueet al., 2006; Ehrlich and Malinow, 2004; Schluter et al., 2006).Knockout mice have helped delineate the different roles of PSD-MAGUKs in synaptic plasticity, by illustrating redundancy as well asspecificity in the various protein associations (Beıque et al., 2006;Carlisle et al., 2008; Cuthbert et al., 2007; El-Husseini et al., 2000b;Elias et al., 2008; McGee et al., 2001; Migaud et al., 1998; Vickerset al., 2006). PSD-95-null mice survive, but animals older than twopost-natal weeks have learning deficits (Migaud et al., 1998).Differences between null mice and controls are generally absentearly in development because of the high SAP-102 expression (Eliaset al., 2008). Given that PSD-95 knockout mice display reduced LTPand AMPA-mediated synaptic transmission (Beıque et al., 2006;Carlisle et al., 2008; El-Husseini et al., 2000b; Elias et al., 2008), PSD-95-dependent AMPA receptor loss may underlie learning deficits,and may be a pathogenic mechanism in AD.

2.2. PSD-MAGUK protein expression in AD

Altered neuronal expression of PSD-MAGUKs in the AD brainhas been posited to modulate the susceptibility of neurons to

glutamate-evoked degeneration. A loss of PSD-MAGUKs from thePSD, or altered interactions between glutamate receptors and theirscaffolding proteins, might be attributable to lower NMDA- orAMPA-receptor subunit levels. There are selective local differencesin PSD-95 expression in AD brain tissue obtained at autopsy (Gylyset al., 2004; Leuba et al., 2008a,b). PSD-95 levels are altered, and SAP-102 expression is reduced, in pathologically vulnerable regions ofthe AD brain, in ways that reflect the severity of disease pathology(Proctor et al., 2010). Cultured neurons harvested from transgenicmice that express mutant amyloid precursor protein (APP) showreduced protein levels of both PSD-MAGUKs and AMPA receptors(Almeida et al., 2005; Cha et al., 2001). Variations in PSD-MAGUKconcentrations in pathologically affected and spared regions of ADbrain are consistent with the pattern of glutamate receptor changes(Gong et al., 2009; Hynd et al., 2004a,b; Wakabayashi et al., 1999),but a direct correlation has not been confirmed.

The ablation of these synaptic proteins can be replicated byadministering pathological concentrations of Ab protein to wild-type cultured neurons (Almeida et al., 2005; Liu et al., 2010). Thishighlights a possible central role for Ab in deregulating synapticproteins, leading to altered neuronal function. A link betweencirculating soluble oligomeric Ab and lower glutamate receptorand PSD-MAGUKs levels in AD could provide a mechanism for LTPdisruption and consequent memory impairment.

2.3. NMDA receptor changes in AD

As NMDA receptor activity is necessary for hippocampal LTP,receptor loss is likely to affect plasticity in early stages of AD. Levelsof expression of certain subunit protein and mRNA isoforms of theNMDA receptor, i.e., NR1 variants containing the N-terminalcassette as well as NR2A and NR2B subunits, are selectivelyreduced in autopsy tissue (Bi and Sze, 2002; Hynd et al., 2004a,b).NR2A and NR2B are the most abundant of the four NMDA NR2subunits in the CNS. NR2A and NR2B expression levels vary duringdevelopment, and differ by brain region and subcellular localiza-tion. NR2A-containing NMDA receptors are located primarily atsynaptic sites, whereas NR2B-containing receptors are locatedextra-synaptically. These differences couple NR2A- and NR2B-containing NMDA receptors to distinct signal transduction path-ways. Substantial evidence now indicates that of the NR2 subunits,NR2B makes the major contribution to neurodegenerative andapoptotic pathways, whereas NR2A mediates neuroprotectivepathways (Liu et al., 2004). Loss of particular subunits maypredispose neurons to excitotoxicity; a decline in NR2A-containingNMDA receptors would reduce transcription of pro-survival genesby down-regulating cAMP response-element binding protein(CREB) signaling (Chen et al., 2008). Biochemical and immunoflu-orescence microscopy findings suggest that the loss of NMDAreceptors may be triggered by Ab. Confocal microscopy hasrevealed that Ab co-localizes with PSD-95 (Cowburn et al., 1997;Dewachter et al., 2009; Lacor et al., 2004), suggesting that Ab maytarget, or be generated from, synapses that express NMDAreceptors. Ab oligomers promote NMDA-receptor endocytosis incultured rat hippocampal neurons (Almeida et al., 2005; Roselliet al., 2005; Snyder et al., 2005). Ab oligomers bind and activatea7-nicotinic receptors promoting protein phosphatase 2B (PP2B)activity. This PP2B then dephosphorylates the tyrosine phospha-tase STEP. Active-STEP then dephosphorylates the c-terminalY1472 residue of the NR2B subunit, promoting NR2B traffickingaway from the surface (Fig. 1; Snyder et al., 2005). STEPconcentrations are elevated in both AD transgenic mouse modelsand in the brains of AD subjects (Chin et al., 2005; Kurup et al.,2010). Together, these Ab-evoked changes in NMDA receptorproteins would reduce synaptic strength and disrupt mechanismsof plasticity, and could underlie Ab-induced changes in LTP.

D.T. Proctor et al. / Progress in Neurobiology 93 (2011) 509–521 511


2.4. AMPA receptor changes in AD

The AMPA receptor subunits GluR1, GluR2 and GluR2/3 aresignificantly reduced in pathologically vulnerable regions of theAD brain (Armstrong et al., 1994; Aronica et al., 1998; Carter et al.,2004; Garcia-Ladona et al., 1994; Ikonomovic et al., 1997; Thornset al., 1997; Wakabayashi et al., 1994). Quantitative autoradiogra-phy in the CA1 and parahippocampal gyrus revealed that AMPA-receptor binding was lower in severe AD cases than in healthy, age-matched controls (Dewar et al., 1991). AD-associated depletions ofAMPA receptor subunits vary with brain area and disease severity(Carter et al., 2004; Wakabayashi et al., 1994). Specifically, in thesubiculum, which is vulnerable to pathological changes in AD,Carter et al. (2004) found significant changes in the levels of GluR2and GluR2/3 proteins. Altered AMPA receptor currents thatcorrelate with the reduced GluR2/3 immunoreactivity precedeNFT deposition and synapse loss (Ikonomovic et al., 1997). WhileGluR1 protein levels in the subiculum are reportedly reduced insevere AD (Armstrong et al., 1994; Schaffer and Gattaz, 2008;Wakabayashi et al., 1994; Yasuda et al., 1995), no correlationbetween GluR1 subunit expression and Braak staging was found

(Carter et al., 2004). This disparity needs to be addressed, althoughit aligns with the observation that plaque deposition does notcorrelate with neuronal dysfunction.

AMPA receptors display rapid turnover. Assays of fluorescencerecovery after photobleaching (FRAP) show that up to 50% ofAMPA-receptor GluR2 subunits on the spine surface are exchange-able (Ashby et al., 2006). When surface AMPA receptors arepermanently inactivated, the recovery of maximal AMPA-mediat-ed currents through activity-dependent recruitment from extra-synaptic pools occurs within a few tens of seconds. In contrast,NMDA receptor recovery takes many minutes (Adesnik et al., 2005;Nilsen and England, 2007). The mobile dynamics of AMPAreceptors allows them to respond rapidly to synaptic inputs andfacilitates prompt plastic changes in synaptic strength.

Aside from SAP-97 which directly binds to AMPA receptors(Sans et al., 2001), PSD-MAGUKs regulate AMPA receptor traffick-ing by recruiting receptors from extra-synaptic sites to the activezone through interactions with the transmembrane AMPAreceptor regulatory proteins (TARPs), the most notable exampleis stargazin (Fig. 1; Schnell et al., 2002). The PSD-95–stargazininteraction is essential for AMPA receptor stabilization at the PSD.

Fig. 1. Proposed mechanisms of Ab-evoked toxicity modulated by NMDA receptor–PSD-MAGUK interactions. Ab oligomers enhance the pre-synaptic release of glutamate

together with the simultaneous blockade of glutamate uptake by astrocytes through glutamate transporters. Excitotoxic levels of glutamate in the synaptic cleft diffuse away

from active sites where they can bind to and activate extra-synaptically located NR2B-containing NMDA receptors. Extra-synaptic NR1/NR2B receptor hyperactivity of these

receptors induces calpain digestion of synaptic NR2A subunits and scaffolding proteins (Gascon et al., 2008). Extra-synaptic NR1/NR2B receptor activity reduces CREB

signaling and hence reduces transcription of pro-survival gene transcription. Elevated levels of glutamate activate post-synaptic glutamate receptors, which initiate

neurotoxic pathways through interactions with the PSD-MAGUK scaffolding molecules including the overproduction of NO. Ab is co-localized to NMDA-receptor- and PSD-

95-positive puncta and may enhance NMDA receptor activity by up-regulating Fyn kinase phosphorylation of the T1472 residue of NR2B (Ittner et al., 2010). Conversely, Abalso binds and stimulates the a7 nicotinic receptor, which leads to the ubiquitin-proteasomal degradation of NMDA receptors and PSD-95 through dephosphorylating residue

1472 of the NR2B subunit by STEP (Snyder et al., 2005). This may contribute to the synaptic dysfunction and plasticity deficits in early-stage AD. All glutamate receptor

trafficking and signaling cascades are dependent on PSD-MAGUK organization. Inhibitors of the NR2B–PSD-MAGUK interaction may have therapeutic significance in

neurodegenerative diseases by preventing excitotoxic signaling events and neuronal death.



Over-expression of mutant stargazin in cultured neuronsdecreases the time AMPA receptors spend at the synapse (Batset al., 2007). PSD-95 expression orchestrates dendritic spinearchitecture and synaptic outgrowth (Steiner et al., 2008).Biophysical modeling has demonstrated that spine morphologyand spine neck geometry influence glutamate receptor diffusionand exchange at the synapse (Ashby et al., 2006; Holcman andTriller, 2006). A mechanism that accounts for AMPA receptorreduction in the AD brain remains elusive. Considering that alteredsynaptic morphology is a neuropathological feature of AD, it isarguable that altered PSD-MAGUK expression might affect AMPAreceptor dynamics in AD. It is also possible that a reduction in PSD-95–stargazin interactions could affect rapid AMPA receptortrafficking in AD.

2.5. Ab-evoked LTP changes in AD

LTP in the hippocampus CA1 and entorhinal cortex, regions thatare central to memory formation, is highly perturbed in AD(Battaglia et al., 2007; Rowan et al., 2003). Synaptic failure mayprecipitate LTP deficits and the deterioration of memory. Inconsequence, AD is now regarded as a disease of synapticdysfunction, although the origin of this is debated. Although Abplaques may be merely markers (‘‘tombstones’’) of pathologicalprocesses that occur early in the disease, there is substantialevidence that the neurotoxic, soluble oligomer forms of Ab, ofwhich Ab42 is the predominant species, can directly triggersynaptic dysfunction and disrupt synaptic plasticity (Mucke et al.,2000; Selkoe, 2002). Several reviews outline how LTP is impairedby Ab in AD, and the evidence for a likely causal relationship(Arendt, 2009; Gasparini and Dityatev, 2008; Parameshwaranet al., 2008; Selkoe, 2002).

Microinjection of conditioned media containing human Aboligomers naturally secreted from cultured Chinese hamster ovarycells into the CA1 region of anesthetized rats prevents theinduction of LTP by high-frequency stimulation (Walsh et al.,2002). LTP is impaired in CA1 hippocampal slices of tripletransgenic AD mice that display Ab plaques, NFTs, and neuronalloss (Oddo et al., 2003). In human AD subjects, LTP is disrupted inhippocampus and entorhinal cortex (Walsh et al., 2002). Severememory loss is an early neuropsychiatric symptom of AD. In vivo

application of Ab from APP mutant cell lines produces memorydeficits and altered behavior in rats (Selkoe, 2008). Whenpicomolar concentrations of Ab are applied to organotypichippocampal slices they markedly reduce dendrite density andthe number of active synapses (Shankar et al., 2007). Theaberrations in LTP caused by Ab occur prior to synaptic loss andare a possible early trigger for neurodegeneration.

2.5.1. Ab induced LTP deficits in AD via altered NMDA receptor-PSD-

MAGUK interactions

Although the mechanism underlying altered NMDA receptorand PSD-MAGUK expression in AD is not known, the interactionbetween presenilin-1 and PSD-95 is suggestive of a causative role(Xu et al., 1999). A number of independent observations supportthe idea that Ab targets glutamatergic transmission in particular,to reduce synaptic activity, underlie LTP deficits, and ultimatelylead to synaptic loss (see Fig. 1). This is consistent with theobservation that circulating Ab oligomers target synapses thatexpress NMDA receptors (Roselli et al., 2005; Shankar et al., 2007).Ab inhibits glutamate uptake by cultured astrocytes whichcontributes to the diffusion of glutamate from the vicinity of theactive zones to extra-synaptic sites where it can activate NR2B-containing NMDA-receptors (Fernandez-Tome et al., 2004; Li et al.,2009; Matos et al., 2008; Parpura-Gill et al., 1997). Ab oligomersenhance stimulus-coupled glutamate release from nerve-ending

particles and increase Ca2+ influx into cultured hippocampalneurons (Bobich et al., 2004; Chin et al., 2007; Kabogo et al., 2008),which would predispose spines to excitotoxic pruning. Calciumhomeostasis is disrupted, to excitotoxic levels, in neuronal culturesexposed to Ab (Mattson et al., 1992), further confirming a centralpathogenic role for soluble Ab species. Although glutamatereceptor loss may contribute to LTP deficits in early AD, it isplausible to posit that accumulation of high Ab concentrationswould generate excitotoxicity through remaining NR2B receptorsin severe AD. The administration of an NMDA receptor antagonistcan prevent Ab-evoked synaptic failure (de Felice et al., 2007;Nakamura et al., 2006).

Given the importance of NMDA receptors and PSD-MAGUKs inaugmenting LTP, and their concurrent loss in the same regions,glutamate-mediated excitotoxicity modulated by Ab may con-tribute to synaptic degeneration and plastic changes (Scheff et al.,1990). Mitigating excitotoxicity may underlie the success of drugssuch as the non-competitive, low-affinity NMDA receptor antago-nist memantine that target glutamate toxicity. Klyubin et al. (2009)demonstrated that memantine, which is approved by the FDA forthe treatment of moderate to severe AD, inhibits Ab-inducedsynaptic failure. Memantine slows disease progression in subjectswith moderate to severe Alzheimer’s disease (McShane et al.,2006). Unfortunately, at therapeutic doses both in vivo and in vitro

the drug not only blocks the disruptive effects of Ab on synapticplasticity and learned behavior but also attenuates normal LTP.This may explain why only modest benefits have been reportedwith memantine treatment. It has been proposed that agents thatare more selective for NMDA receptor subtypes would bebeneficial therapeutic agents (Klyubin et al., 2009). For example,NR2B–specific antagonists demonstrate the greatest effect inattenuating Ab-toxicity (Liu et al., 2010).

On the other hand, Ab-evoked NMDA receptor loss mayexacerbate neurodegeneration by enhancing the production ofadditional Ab protein. NMDA receptor stimulation under normalphysiological activity is implicated in non-amyloidogenic proces-sing (Marcello et al., 2008). It promotes the initial cleavage of APPby a-secretases, thereby limiting the production and extracellularrelease of toxic Ab species that is associated with the initial APPcleavage by b-secretases (Hoey et al., 2009). A disintegrin andmetalloproteinase 10 (ADAM10), the most well-known a-secre-tase implicated in the non-amyloidogenic processing of synapticAPP, is trafficked to PSD sites following NMDA receptor activity.ADAM10 binds to SAP-97, an interaction that is essential for thedelivery of ADAM10 to the plasma membrane and also controls thesubcellular localization and activity of the secretase (Marcelloet al., 2007). Disrupting the SAP-97–ADAM10 interaction attenu-ates the non-amyloidogenic processing of APP and promotes Abaccumulation (Marcello et al., 2007). SAP-97–ADAM10 complexesare reduced in AD autopsy tissue (Marcello et al., 2010);pharmacological blockade of the SAP-97–ADAM10 interaction isthe basis of a recent model of sporadic AD (Epis et al., 2010).Unfortunately, chronic NMDA receptor stimulation in hippocam-pal cultures that may occur under pathological conditions alsostimulates Ab production by inhibiting a-secretase activity. Thesediscrepancies require clarification (Lesne et al., 2005).

2.5.2. Ab induced LTP deficits in AD via altered AMPA receptor–PSD-

MAGUK interactions

The effects of Ab on AMPA receptors in AD brain might also beresponsible for the simultaneous loss of NMDA receptors (Szegediet al., 2005). PSD-95 knockout mice display reduced AMPAreceptor activity, and PSD-95 expression is reduced in ADtransgenic mouse models. Hence, the loss of post-synapticscaffolding protein could contribute to AMPA receptor-dependentLTP deficits in AD. Further research is needed to resolve



controversies over AMPA receptor-density and functional dis-turbances in AD, and over the influence of disease-dependent PSD-MAGUK expression on AMPA-receptor concentrations and synap-tic localization.

These aberrations in synaptic function precede both amyloidplaque and NFT formation, and are key processes underlying earlyclinical manifestation of cognitive decline (Funato et al., 1999;Hartl et al., 2008; Selkoe, 2002; Walsh and Selkoe, 2004).

In addition to LTP, PSD-95 plays a vital role in LTD(Bhattacharyya et al., 2009). PSD-95 augments the removal ofthe AMPA receptor from the synapse by bringing it into closeproximity with specific kinases and phosphatases through bindingto the scaffolding protein A Kinase Anchoring Protein 150(AKAP150; Bhattacharyya et al., 2009). An L460P point mutationin PSD-95, which prevents binding to AKAP150, completelyabolishes NMDA receptor-triggered endocytosis of AMPA recep-tors (Fig. 1; Bhattacharyya et al., 2009).

In hippocampal neurons expressing GFP-tagged AMPA receptorsubunit GluR1, tetanus stimulation leads to the trafficking of GluR1from free cytoplasmic pools to the membrane surface, an effectthat is blocked by pre-incubation with the NMDA antagonist 2-amino-5-phosphonopentanoic acid (Shi et al., 1999; Fig. 1). CaMKIIbinds to specific subunits of the NMDA receptor for which PSDscaffolding proteins dictate expression and localization within thePSD. AMPA receptor activity, localization, and trafficking areultimately dependent on the subunit composition of NMDAreceptors, and hence on PSD-MAGUK expression. The possessionof particular subunit combinations may determine the degree ofsusceptibility of a post-synaptic neuron to glutamate-evokedexcitotoxicity.

Gu et al. (2009) showed that administration of neurotoxic Ab42

fragments to hippocampal neurons interrupts AMPA receptortrafficking and function, leading to the removal of AMPA receptorsfrom the synapse. Similar data showing loss of AMPA receptors fromthe membrane were observed in an APP transgenic mouse model ofAD. Since the regulation of AMPA receptors is crucial for NMDA-mediated LTP, Ab-induced disruption of AMPA trafficking and/orexpression could account for the observed changes to LTP and spineintegrity, and thus the decline in NMDA expression. Intraneuronalelevations in Ca2+ concentration, as measured by the fluorescence ofthe ratiometric Ca2+ dye FURA-2 following application of Abfragments, is prevented by pre-incubating the cultures with AMPAreceptor antagonists (Blanchard et al., 2004). This suggests that Abfragments could modulate AMPA receptors to promote the entry ofexcitotoxic levels of Ca2+ into neurons. Altered AMPA receptorregulation may exacerbate glutamate-evoked toxicity.

2.6. PSD-MAGUK-dependent glutamate signaling changes in AD

2.6.1. CaMKII

During high-frequency stimulation that generates LTP, Ca2+

influx through NMDA receptors activates CaMKII (Barria et al.,1997a,b; Derkach et al., 1999; Fukunaga et al., 1993; Lisman et al.,2002; Malenka and Nicoll, 1999; Mammen et al., 1997). ActivatedCaMKII mediates the insertion of AMPA receptors into the synapticmembrane (Lisman et al., 2002; Malenka and Nicoll, 1999; Shiet al., 1999; Fig. 2). Once inserted into the membrane, CaMKIIphosphorylates AMPA receptors and enhances channel conduc-tance by�50%, thus promoting LTP (Barria et al., 1997a,b; Derkachet al., 1999; Mammen et al., 1997).

Levels of total and activated forms of CaMKII are reportedlyaltered in AD brain, and in hippocampal cultures treated with Ab(Amada et al., 2005; Tardito et al., 2007; Zhao et al., 2004), althoughconcentrations of CaMKII protein in the PSD do not differsignificantly between AD cases and aged-matched controls(Simonian et al., 1994; Tannenberg et al., 2006). CaMKII occurs

in several subcellular compartments that provide specificity andefficacy in signaling. CaMKII pools are differentially affected duringAD (Gu et al., 2009). Activated CaMKII levels in cytoplasm are up-regulated in AD, whereas the total amount of activated CaMKIIassociated with the surface membrane is reduced in culturesexposed to Ab (Amada et al., 2005; Gu et al., 2009; Tardito et al.,2007; Zhao et al., 2004). The direction of CaMKII regulation seemsto depend on the concentration of Ab, and to vary with acute vs

chronic application (Tardito et al., 2007). In cultures that undergolong-term Ab exposure, which is probably more analogous toconditions in AD, the activity of CaMKII located in the PSD is up-regulated. NMDA receptor activity is necessary for Ab-evokedaberrations in CaMKII activity; however, the mechanism underly-ing Ab-dependent CaMKII regulation is unknown.

Following the repeated NMDA receptor activation that isthought to occur in AD, CaMKII-dependent phosphorylation of theserine-73 (S73) residue of PSD-95 induces rapid trafficking of PSD-95 away from the PSD by dissociating PSD-95 from the NR2Asubunit (Gardoni et al., 2006). In normal physiological conditionsthis mechanism is responsible for terminating the growth ofdendritic spines during synapse development (Steiner et al., 2008).Elevated levels of the activated form of CaMKII in the PSD in ADcould drive the removal of PSD-95, affect glutamate receptor andspine stability, and contribute to the low PSD-95 concentration.The extent of PSD-95 phosphorylation has yet to be investigated inAD. Agents that prevent the phosphorylation of S73 in PSD-95might be novel therapeutic candidates for the treatment of AD.

CaMKII and PSD-MAGUKs compete for binding sites on theNMDA receptor C-terminus (Gardoni et al., 2002). PSD-95 bindingto NMDA receptors prevents CaMKII association and de-activatesCaMKII bound to NMDA receptors after periods of high-frequencystimulation. This mechanism prevents CaMKII signaling fromreaching excitotoxic levels. Reduced neuronal PSD-95 concentra-tions in AD would result in sustained CaMKII activation andneurotoxicity. Gardoni et al. (2002) induced neuronal degradationin hippocampal cultures by knocking down PSD-95 expressionwith anti-sense oligonucleotides, and demonstrated the possibleimportance of this mechanism in AD. CaMKII-induced PSD-95decline in AD would further exacerbate synaptic dysfunction bypromoting CaMKII-dependent neuronal toxicity.

2.6.2. Phosphatidylinositol 3-kinase

NMDA receptor stimulation augments AMPA-receptor traffick-ing to the membrane by activating the PI3K that is bound to it. Indissociated hippocampal neurons, Ca2+ influx up-regulates the G-protein Ras through CaMKII (Stornetta and Zhu, in press), whichphosphorylates receptor-bound PI3K (Man et al., 2003). ActivatedPI3K phosphorylates phosphatidylinositol-(4,5)-bisphosphate(PIP2) to form phosphatidylinositol-(3,4,5)-trisphosphate (PIP3),which facilitates the fusion of vesicles that contain AMPA-receptor–PI3K complexes with the membrane. PIP3 is necessary for AMPAreceptor clustering (Arendt et al., 2010). AMPA receptor insertionfollowing stimulation, as measured by confocal microscopy and cell-ELISA assays, is blocked by pre-incubating neurons with the PI3Kinhibitors wortmannin and LY294002 (Man et al., 2003).

Although it has not yet been confirmed in human AD autopsytissue, it is likely that PI3K activity would be reduced because itscounterpart, phosphatase and tensin homologue deleted onchromosome 10 (PTEN), which antagonizes PI3K, is dysregulated(Griffin et al., 2005; Sonoda et al., 2010) as are its upstreamregulatory proteins including Ras (Stornetta and Zhu, in press).PI3K activity plays a role in a number of cellular events in additionto AMPA receptor trafficking, which include cell growth, prolifera-tion, and survival via the activation of the PI3K–Akt–mTORpathway (Song et al., 2005). PI3K–Akt–mTOR signaling negativelyregulates extrasynaptic NMDA receptor activity (Ning et al., 2004).



Disrupting PI3K–Akt–mTOR signaling in AD through increasedPTEN activity would vitiate the modulation of synaptic activity aswell as induce other hallmarks of degeneration through the down-regulation of pro-survival mechanisms (Man et al., 2003; Sonodaet al., 2010).

The suppression of PTEN expression with siRNA in culturedhippocampal neurons enhances Akt phosphorylation and protectsagainst excitotoxic neurodegeneration through activated extra-synaptic NMDA receptors (Ning et al., 2004). PTEN binds NR1subunits, but probably also interacts indirectly with the NR2Bsubunit because PTEN co-immunoprecipitates with NR1/NR2B butnot NR1/NR2A receptors (Ning et al., 2004). It is likely thatstimulation of NR2B-containing NMDA receptors enhances PTENactivity. NMDA receptor stimulation potentiates the recruitment ofPTEN to the PSD by enhancing PTEN binding to PSD-95 (Juradoet al., 2010). PTEN could associate with NR2B via PSD-95.

Activated PI3K initiates the PI3K–Akt–mTOR pathway to inducePSD-95 protein expression (Yang et al., 2008). Pools of PSD-95mRNA are located close to the synapse in the PSD. NMDA receptor-activated production of PSD-95 protein is normally rapid, allowingthe post-synaptic neuron to quickly exhibit plastic changes(Akama and McEwen, 2003; Lee et al., 2005). Reduced PIP3

production resulting from lower concentrations of active PI3Kwould deplete PSD-95 in spines (Arendt et al., 2010). This couldmediate Ab-dependent PSD-95 reductions and dysregulatedAMPA receptor delivery to the membrane in AD. A number of

lines of evidence implicate the direct interference of Ab in PI3K–Akt–mTOR signaling. Cultured neurons exposed to Ab exhibitdown-regulated phosphorylation of several PI3K–Akt–mTORpathway targets and substrates (Chen et al., 2009). This has beenconfirmed in pathologically affected brain regions in AD subjects(Lafay-Chebassier et al., 2005).

Ab might interfere with PI3K signaling by promoting NR2B-containing NMDA receptor activity. Acute treatment of cortico-hippocampal cultures with Ab leads to increased PI3K activity thatis blocked with the NR2B subunit-specific NMDA receptorantagonist ifenprodil. PI3K activity declines to normal levelsfollowing extended periods of Ab treatment. However, chronic Abexposure significantly down-regulates Akt phosphorylation. Thelatter coincides with both the appearance of amyloid plaques andthe onset of cognitive decline in APP transgenic mice (Abbott et al.,2008). Neurons over-expressing mutant presenilin 1 (PS1) haveinterrupted PI3K–Akt–mTOR signaling. PS1 activates PI3K activity,so the loss of PS1 function in some familial forms of AD is likely tocontribute to these changes (Baki et al., 2004).

Insulin stimulates PSD-95 production via the PI3K–Akt–mTORpathway. Ab induces significant loss in surface insulin receptors inculture (Zhao et al., 2008) and insulin resistance is recorded in ADand MCI subjects (Luchsinger and Gustafson, 2009; Odetti et al.,2005). It is expected that down-regulated insulin receptor activitycontributes to reduced PSD-95 production and expression ofneuronal survival genes through PI3K–Akt–mTOR signaling.

Fig. 2. Proposed mechanisms for PSD-95 loss and LTP deficits in AD. Ab down-regulates PI3K–Akt–mTOR signaling in AD via inhibiting insulin receptor activity and promoting

PTEN phosphatase activity through unknown mechanisms. Disrupted PI3K–Akt–mTOR signaling may inhibit transcription of scaffolding protein genes and therefore reduce

protein concentrations in affected neurons. Dysregulated PI3K–Akt–mTOR signaling in AD may also promote a pro-apototic response and increase neurotoxicity through up-

regulating NMDA receptor activity. CaMKII activity is upregulated in some sub-cellular regions of AD affected neurons that can phosphorylate PSD-95 protein and promote its

degradation. Dysregulated CaMKII activity may contribute to a reduction in Ras activity observed in AD. This would further exacerbate disrupted AMPA receptor trafficking

dynamics caused by a dyregulation of PI3K and PTEN concentrations and the inability to convert PIP2 to PIP3.



2.7. PSD-MAGUK–glutamate receptor interactions in excitotoxicity

The progression of PSD-MAGUK changes in AD is notmonotonic. Rather than a steady decline in protein expression,there is a biphasic response linked to neuropathological stage(Proctor et al., 2010), and there are regional variations. During thecourse of the disease expression may be briefly elevated,particularly at mild stages. In AD autopsy studies, samples areoften only available from subjects at advanced stages of thedisease, so it is difficult to rule out the possibility that PSD-MAGUKand glutamate receptor losses result from the losses of synapsesand neurons. In-vitro cell-animal models of AD suggest thatreductions in PSD-MAGUK linked to synaptic dysfunction triggerplastic changes early in the disease cycle, but there are significantspecies differences and more research is required in humansubjects at early stages of AD. The biphasic response in PSD-MAGUK expression is similar to trends in the expression of othersynaptic proteins such as synaptophysin (Mukaetova-Ladinskaet al., 2000). Consistent with this, there have been some reports ofan up-regulation of PSD-MAGUK protein expression in thedorsolateral prefrontal and entorhinal cortices in end-stage AD(Leuba et al., 2008a,b).NMDA receptor-mediated activity triggersmany forms of LTP; NMDA receptor antagonists prevent LTP(Malenka and Nicoll, 1999; Malenka and Bear, 2004). There areseveral means by which NMDA receptors control LTP. NMDAreceptor stimulation initiates AMPA receptor insertion into thesynaptic membrane by an activated-CaMKII-dependent mecha-nism (above). AMPA receptor delivery can be blocked in neuronalcultures by pre-incubation with either NMDA receptor antagonistsor CaMKII inhibitors. Administration of the CaMKII inhibitor Ant-AIP-2 affects the concentration and subcellular localization of theNMDA receptor by a mechanism that is specific for the NR2Bsubunit (Gardoni et al., 2009). Active CaMKII binding to NR2B isrequired for hippocampal LTP, suggesting that CaMKII maymodulate glutamate-receptor trafficking (Barria and Malinow,2005).

NMDA receptors bind both CaMKII and PSD-95 and bring theseproteins into close apposition. NMDA receptor activation promotesfurther PSD-95 trafficking to the synapse, which also disrupts PSD-95 homeostasis (Yoshii and Constantine-Paton, 2007). In contrastto NR2A, PSD-95 phosphorylation by CaMKII has no effect on theinteraction of PSD-95 with NR2B (Gardoni et al., 2006). Dysregu-lated PSD-95 metabolism could generate pathological intraneur-onal concentrations of Ca2+ and up-regulated NR2B-PSD-95interactions. AMPA receptor insertion is ultimately dependenton the subunit composition of NMDA receptors, and therefore onsynaptic compartmentalization and the localization of scaffold-protein expression.

2.7.1. NR2B–PSD-MAGUK-induced excitotoxicity

Glutamate excitotoxicity correlates more closely with in-creased levels of NR2B, rather than NR2A, subunits (Cheng et al.,1999; Mizuta et al., 1998), although over-activation of NR2A-containing NMDA receptors may contribute to excitotoxic levels ofintracellular Ca2+ ions, an effect that is exacerbated by Ab (Wu andHou, 2010). For the most part, activation of extra-synapticallylocated NMDA receptors is the predominant path to neurotoxicity(Hardingham et al., 2002). The excitotoxic characteristics of NR2B-containing receptors stem from longer current-decay times, whichallow greater influx of Ca2+ ions than the other NR2 subtypes (Zhaoand Constantine-Paton, 2007). Activated NR2A-containing NMDAreceptors are associated with induction of CREB activity and theenhancement of CREB-dependent pro-survival gene transcription(Chen et al., 2008). Activated NR2B-containing NMDA receptors areassociated with pathways stopping the CREB-dependent pathways(Hardingham et al., 2002). Stimulation of NR2B-containing NMDA

receptors leads to calpain digestion of the NR2A subunit C-termini,allowing the truncated NR2A subunit to maintain association withNR1, but preventing the induction of activated-receptor signaling(Gascon et al., 2008). This process would exacerbate CREB signalinginhibition. NR2B is the most abundant NR2 subunit in thehippocampus, an area that degenerates markedly in AD (Hyndet al., 2004b).

NR2B-containing NMDA receptors demonstrate greater affinityfor SAP-102 than for other PSD-MAGUK proteins. A developmentalswitch from a majority of NR2B-containing NMDA receptors toNR2A-containing NMDA receptors, which enhances the temporalprecision of glutamate-mediated transmission, follows a concomi-tant increase in PSD-95 and decrease in SAP-102 in the rodent CNS(Flint et al., 1997; Liu et al., 2004; Stocca and Vicini, 1998;Takahashi, 2005). These changes in NMDA receptor compositionconform to a lower susceptibility to NMDA receptor-mediatedneurotoxicity in neuronal cultures from younger animals (Zhouand Baudry, 2006). Post-natally, SAP-102 expression increasesgradually up to around day P12 in infant rats (Sans et al., 2000).Rising SAP-102, and hence NR2B, expression during this periodcoincides with an increase in glutamate-evoked neurotoxicity.Administration of NR2A-specific antagonists to cultured neuronsdoes not limit excitotoxic damage. Because SAP-102 is stronglyassociated with NR2B, this interaction may be essential fordegeneration. Conversely, changes in SAP-102 expression couldbe implicated in disease processes that involve NR2B.

Changes in scaffold-protein expression are linked to severalneurological diseases. For example, SAP-102 gene mutations areassociated with X-linked mental retardation (Tarpey et al., 2004;Zanni et al., 2010). These mutations are responsible for theintroduction of premature stop codons into the SAP-102 codingregion, resulting in loss of SAP-102 function. In bipolar disorder,SAP-102 expression is reduced in the same regions affected in AD(McCullumsmith et al., 2007). Similar reductions in the expressionof SAP-102 and other PSD-MAGUKs have been found in schizo-phrenia (Beneyto and Meador-Woodruff, 2008; Clinton andMeador-Woodruff, 2004; Kristiansen and Meador-Woodruff,2005) and epilepsy (Qu et al., 2009). The neuropsychiatriccharacteristics of schizophrenia may stem from impaired NMDAreceptor function. The origins of this hypofunction are not known,although reduced SAP-102 protein and transcript expressioncontributing to altered glutamatergic signaling is a plausibleexplanation for some of the abnormalities.

Epilepsy is linked to the induction of excitotoxic pathways thatoccur in AD. Seizures are a feature of several APP transgenic miceand a frequent symptom in some AD subjects (Minkeviciene et al.,2009; Palop et al., 2007; Palop and Mucke, 2009). Loss of glutamatereceptors and associated scaffolding proteins in epilepsy may be afunction of increased glutamate activity leading to increases inreceptor endocytosis and/or degradation. Over-stimulation ofremaining surface receptors could activate excitotoxic pathways,enhance NO production, and induce immunological responses (Raoet al., 2010).

2.7.2. nNOS–PSD-MAGUK-induced excitotoxicity

The phenotypes of knockout mice offer clues to an involvementof PSD-MAGUKs in excitotoxicity and neurodegeneration. Neuronsdeficient in PSD-95 display reduced vulnerability to excitotoxicity;in contrast, when SAP-102, PSD-93 or SAP-97 expression isknocked down neurons remain vulnerable (Cui et al., 2007). Thisimplies there is a neurotoxic mechanism specifically related toPSD-95 that is independent of the PSD-95–NR2A interaction.NMDA receptor activity can promote synaptic trafficking of AMPAreceptors to active sites through its association with neuronalnitric oxide synthase (nNOS; Fig. 1) and the production of theintracellular messenger, nitric oxide (NO; Rameau et al., 2007).



nNOS interacts indirectly with NMDA receptors, particularly thosecontaining an NR2B subunit, by binding PSD-95 through its PDZdomain (Brenman et al., 1996). NO production is necessary for LTP,and inhibitors of nNOS prevent the induction of LTP (Doyle et al.,1996; Schuman and Madison, 1991). If PSD-95 protein levelsdecline, as is the case in AD, this may contribute to a loss in LTP.

Conversely, high concentrations NO are neurotoxic. If PSD-95-NR2B interactions are markedly elevated, excess NO productionmay induce toxic responses in some neurons. Neurodegenerationattributable to nNOS activation has been reported in AD, andneurons expressing nNOS are particularly vulnerable to degenera-tion in the disease (Thorns et al., 1998). Inhibiting NMDA-receptoractivation or preventing the interaction of NMDA receptors withPSD-95 blocks NO-dependent neurodegeneration in models ofstroke (Aarts et al., 2002; Bredt and Snyder, 1989). Considering thatAb exacerbates neurodegeneration through NMDA receptors,these inhibitors of NMDA receptor–PSD-95 interactions may havea role to play in the treatment of AD, particularly in severe stages.

2.8. PSD-MAGUK inhibitors

Over-stimulation of glutamate receptors, particularly NMDAreceptors, can evoke excitotoxic damage to neurons (Dodd, 2002).Glutamate-mediated excitotoxicity contributes to the selectivedestruction of glutamatergic neurons in pathologically affectedregions of the AD brain. This is the basis for treatment withmemantine, which exhibits highest affinity for NMDA receptorscontaining NR2C subunits. However, the latter subtype is notablyless plentiful in human brain than the highly abundant NR2A andNR2B subunits (Hynd et al., 2004b), and the regional distribution ofNR2A and NR2B subunits conforms more closely with the patternof pathology in AD (Lynch and Guttmann, 2001). Because NMDAreceptors control many synaptic pathways, non-specific antago-nists will have widespread detrimental effects in CNS (Davis et al.,2000; Fix et al., 1993; Morris et al., 1999; Wozniak et al., 1996).

Molecules that affect interactions between scaffolding proteinsand glutamate receptors may offer a more selective-way to targetkey subunits and their specific down-stream pathways induced byreceptor activation, while limiting side effects. Inhibitors of theseinteractions should allow essential glutamate pathways to bemaintained but block those linked to neurotoxicity. Candidatemolecules are being investigated in animal models of ischemicbrain injury such as stroke (Aarts et al., 2002; Bach et al., 2008; Cuiet al., 2007).

Early trials of molecules that inhibit protein-protein interac-tions (as would be necessary for glutamate-receptor–MAGUKcomplexes) were problematic due to the hydrophobic nature of thebinding sites, but it is now known that molecules that blockbinding interactions can be quite small, which offers promise forthe future. The design of compounds currently on trial is based onfindings in rodents. Lead molecules primarily target the interactionbetween the NR2B subunit and PSD-95, and are derived from the C-terminal region of the NR2B subunit attached to the HIV-1 Tatpeptide. This yields a 20-mer peptide that binds to PSD-95 andprevents it from coupling endogenous NR2B, which blocks NMDAreceptor-stimulated NO production. Gardoni et al. (2009) demon-strated that NMDA receptor NR2B (but not NR2A) relocation to thesynapse is prevented by blocking its interaction with PSD-95 witha similar inhibitor, TAT-R2. Similarly, NR2B phosphorylation,which is highly labile and critical for the acquisition of LTP in theCA1 (Moon et al., 1994; Nakazawa et al., 2001; Rostas et al., 1996;Yu et al., 1997), but when elevated can promote excitotoxicintraneuronal levels of Ca2+ ions, can be prevented with thesecompounds. A high level of NMDA-receptor phosphorylation hasbeen quantified in AD autopsy tissue (Salter and Kalia, 2004; Szeet al., 2001).

The current test compound has limited oral bioavailability andblood-brain-barrier permeability. Nonetheless, peptide derivativesoffer a starting point for future therapeutics. Blockers of PSD-95–NMDA receptor interactions have been tested in models of strokeand neuropathological pain with great success in attenuatingexcitotoxic damage to neurons. In these models the compoundsmaintain regular NMDA receptor currents; however, their effectson LTP and plasticity were not investigated (Aarts et al., 2002).

A recent study has shown that compounds that block NR2B-PSD-95 interactions reduce degeneration in cultured neuronstreated with Ab, and improve the survival and memory perfor-mance of Ab-forming APP23 mice (Ittner et al., 2010). Theseencouraging data confirm the potential effectiveness of suchcompounds for treating AD. Although further work will be requiredto determine their effects on synaptic plasticity, experiments inhippocampal cultures suggest that long-term exposure to thesecompounds could have an effect on LTP. Compounds targetingother interactions with PSD-MAGUKs, particularly between SAP-102 and NMDA receptors, could also prove beneficial in ADtreatment.

3. Summary and conclusion

Glutamate receptor expression and activity are modulated byinteractions with post-synaptic scaffolding proteins that augmentthe strength and direction of signal cascades initiated by glutamatereceptor activity. We propose that reduced PSD-MAGUK-gluta-mate receptor interactions found in AD might be responsible forNMDA and AMPA receptor loss in affected synapses and that Ab islikely to play a central role in inducing the loss. Clues from in vitro

cell and animal models of AD indicate that reductions in PSD-MAGUK are linked to synaptic dysfunction and might triggerplastic changes early in the disease cycle. Selective losses ofscaffolding proteins and glutamate receptor subunits may under-pin the region-specific neurotoxicity observed in AD. Speciesdifferences and the lack of characterization of PSD-MAGUKsubtypes and their expression in human subjects with early-stageAD show that more research is required before firm conclusionscan be drawn. Nonetheless, current evidence suggests that scaffoldproteins are promising targets for focused and effective drugtherapies aimed at ameliorating cognitive impairment and declinein AD.

Acknowledgments

Financial support was provided by the Alzheimer’s Association(USA) under grant # RG1-96-005 and the Judith Jane Mason andHarold Stannett Williams Memorial Foundation. DTP was therecipient of a UQ Graduate School scholarship.

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