Amyloid beta peptides and glutamatergic synaptic dysregulation

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Experimental Neurology 210 (2008) 7 – 13 www.elsevier.com/locate/yexnr

Review

Amyloid beta peptides and glutamatergic synaptic dysregulation Kodeeswaran Parameshwaran, Muralikrishnan Dhanasekaran, Vishnu Suppiramaniam ⁎ Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA Received 17 July 2007; revised 3 October 2007; accepted 5 October 2007 Available online 24 October 2007

Abstract Alzheimer's disease (AD) is a major neurodegenerative disorder in which overproduction and accumulation of amyloid beta (Aβ) peptides result in synaptic dysfunction. Recent reports strongly suggest that in the initial stages of AD glutamate receptors are dysregulated by Aβ accumulation resulting in disruption of glutamatergic synaptic transmission which parallels early cognitive deficits. In the presence of Aβ, 2amino-3-(3-hydoxy-5-methylisoxazol-4-yl) propionic acid (AMPA) glutamate receptor function is disrupted and the surface expression is reduced. Aβ has also been shown to modulate N-methyl-D-aspartate receptors (NMDARs) and metabotropic glutamate receptors. The Aβ mediated glutamate receptor modifications can lead to synaptic dysfunction resulting in excitotoxic neurodegeneration during the progression of AD. This review discusses the recent findings that glutamatergic signaling could be compromised by Aβ induced modulation of synaptic glutamate receptors in specific brain regions. Published by Elsevier Inc.

Contents Introduction . . . . . . . . . . . . AMPA receptors . . . . . . . . . NMDA receptors . . . . . . . . . Metabotropic glutamate receptors. Concluding remarks . . . . . . . References . . . . . . . . . . . .

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Introduction Amyloid beta (Aβ) peptides are overproduced and accumulated in Alzheimer's disease (AD), which is the most common form of dementia in elderly population with about 4.5 million patients in the US (Yaari and Corey-Bloom, 2007) and about 4.6 million new cases added each year worldwide (Smith, 2006). AD is strongly age related; however, there are several genetic risk factors responsible for early onset familial AD (Sherrington et al., 1995; St George-Hyslop, 2000). As life expectancy continues to increase with improved medical care, the proportion of ⁎ Corresponding author. Department of Pharmacal Sciences, 401 Walker Building, Auburn University, Auburn, AL 36849, USA. Fax: +1 334 844 8331. E-mail address: [email protected] (V. Suppiramaniam). 0014-4886/$ - see front matter. Published by Elsevier Inc. doi:10.1016/j.expneurol.2007.10.008

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the elderly in the population is expected to increase in the future. Therefore AD is expected to gain increasing significance in terms of economy and public health due to increasing number of patients and high costs associated with patient care. Instigated by this great significance enormous research effort is dedicated to AD research currently and in the recent past. AD shows distinct pathophysiological hallmarks than clinical symptoms. These hallmarks include severe atrophy in the cortex, hippocampus and amygdala (Chan et al., 1999) and the two characteristic lesions: senile plaques composed of deposits of amyloid beta (Aβ) peptides and neurofibillary tangles of hyperphosphorylated tau protein (Lee et al., 2001; Selkoe, 2003). The Aβ peptides are produced as a result of a two step proteolytic cleavage of transmembrane amyloid precursor protein (APP) by β- and γ-secretases. When γ-secretase

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cleavage occurs in the endoplasmic reticulum it produces Aβ1–42 and produces Aβ1–40 in the trans-Golgi network. The APP cleavage by α-secretase is non-amyloidogenic as this enzyme cleaves within the Aβ sequence of APP. The modulation of APP processing is discussed in detail elsewhere (Tang and Liou, 2007). The Aβ1–40 and Aβ1–42 are the most predominant species found in AD brains (Hsieh et al., 2006). Though other sequences like Aβ25–25 have been used extensively in research, the effects of this peptide may be different from the ones found in the brain (Giovannelli et al., 1995). According to the amyloid hypothesis (Hardy and Selkoe, 2002), Aβ peptides are the etiological agents of AD pathology. In particular, among the various assembly forms, oligomeric Aβ has been shown to be very potent in disrupting plasticity mechanisms and causing memory impairment (Barghorn et al., 2005; Cleary et al., 2005; Lesne et al., 2005; Townsend et al., 2006). The amyloid hypothesis is continued to be supported by several reports which utilized animal models of AD with excessive build up of Aβ, and in vitro nerve cells/ tissues subjected to Aβ insult. Increasing evidence suggest that AD and possibly other forms of dementia are due to synaptic pathological processes in which synaptic loss and synaptic dysfunction begin several years prior to severe neuronal loss. In such cases synaptic loss in living AD brain neurons could be as high as 38% and disturbances in APP processing initiate pathologic changes, probably involving synapses (Yao et al., 2003). Synaptic pathology, especially diminished synaptic plasticity in hippocampal Shaffer collateral synapses has been identified as the earliest manifestation of neurodegenerative tauopathies like AD (Yoshiyama, 2007). The notion that synaptic pathology, altered transmission in Shaffer collateral synapses, precedes amyloid plaque formation and overt neuronal atrophy is further supported by research involving transgenic mice over expressing human APP (Larson et al., 1999). An overview of synaptic pathology in AD is provided elsewhere (Yao et al., 2003). Most of these reports have unequivocally shown that excitatory synaptic transmission and plasticity in the hippocampus are compromised in AD pathogenesis. Studies strongly support that cholinergic and glutamatergic excitatory neurotransmitter systems are affected leading to synaptic dysfunction and neurodegeneration in AD. The cholinergic dysfunction in AD has been previously reviewed in detail elsewhere (Sivaprakasam, 2006; Yan and Feng, 2004). Here we present a summary of recent findings that relate to glutamatergic synaptic dysfunction by Aβ peptides during AD progression. AMPA receptors The 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors (AMPARs) are one class of ligand gated ionotropic glutamate receptors in the mammalian brain, which show fast gating kinetics, desensitize rapidly and mediate the rapid glutamatergic synaptic transmission (Dingledine et al., 1999). AMPARs—are essential for synaptic plasticity events like long term potentiation (LTP) and long term depression (LTD) both of which are believed to be cellular correlates of memory regulation (Carroll et al., 1999; Hayashi et al., 2000).

The expression of LTP is believed to be due to increased insertion and enhanced function of AMPARs in the postsynaptic membrane whereas the expression of LTD requires increased removal and decreased function of these receptors (Bredt and Nicoll, 2003; Carroll et al., 1999; Hayashi et al., 2000; Song and Huganir, 2002). Both these plasticity events are strongly related to AD and animal models of AD have been shown to display alterations in synaptic plasticity (Kim et al., 2001). This leads to the hypothesis that changes in postsynaptic AMPAR function and number may play a crucial role in AD pathogenesis. Despite the above findings, the role of AMPARs in AD remains elusive. Recently there has been a surge of research interest which resulted in studies demonstrating downregulation of AMPARs during early AD. It is important to emphasize here that cognitive deficits in early AD, prior to neuronal atrophy, is due to synaptic failure (Selkoe, 2002). Postsynaptic glutamate receptor trafficking and functional alterations along with presynaptic modifications could be prime targets for modulation by Aβ peptide (Parameshwaran et al., 2007). Early reports documented decreased AMPA binding sites in AD (Armstrong et al., 1994; Aronica et al., 1998; Thorns et al., 1997) suggesting a reduction in AMPARs in AD brain. In AD brains as well as in rat embryonic hippocampal primary cultures exposed to Aβ25– 35 caspase activity was high and is attributable to the enzymatic cleavage of AMPAR subunits (Chan et al., 1999) suggesting apoptotic pathways are responsible for reduction in receptor numbers. Interestingly no change in NMDAR subunit levels was found implying that they are not proteolytically cleaved by caspase. This notion is further supported by the fact that AMPAR subunits have potential cleavage sites for caspase-3 and acute exposure of Aβ was sufficient to cause reductions in AMPARs which would argue against a reduction in postsynaptic expression. Since NMDAR subunits were not altered one could assume that calpains may not play a critical role in this process since activation of calpains would result in proteolysis of both AMPAR and NMDAR subunits (Bi et al., 1997; Bi et al., 1998). These reports collectively suggest that an enzymatic degradation process of AMPARs in AD would contribute to the early synaptic loss and function. In addition to promoting selective enzymatic degradation, the Aβ peptides may have direct binding and modulatory effects on AMPARs. Indeed Aβ has been shown to bind with many cell membrane proteins and receptors (Verdier and Penke, 2004). In CA1 neurons iontrophoretically applied Aβ1–42 (mixture of mature fibrils and protofibrils) attenuated AMPA-evoked neuronal firing whereas NMDA-evoked firings were potentiated (Szegedi et al., 2005). In Xenopus oocytes expressing AMPARs, bath application of a low concentration (0.1 μM) of Aβ1–42 slightly suppressed AMPAR currents while Aβ1–40 showed a potentiating effect suggesting AMPARs may have a specific binding site for Aβ (Tozaki et al., 2002). Recent report from our laboratory demonstrated that bath application of micromolar concentrations of Aβ1–42 inhibited AMPAR currents while application of Aβ1–40 was without any effect (Parameshwaran et al., 2007). The differences in the results of these studies could be attributable to the cell type, concentrations of Aβ as well as the aggregation state of the peptide itself.

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However these reports strongly suggest that a direct association between AMPARs and Aβ is possible and could result in modulation of channel properties. Application of Aβ during synaptic plasticity formation could be an interesting approach to assess how this peptide would modify the processes underlying synaptic plasticity. Though altered kinetics of synaptic AMPARs would affect synaptic plasticity, inhibition of increased AMPAR insertion by Aβ could contribute to even stronger attenuation in synaptic plasticity. Toxic effect of Aβ in this perspective seems to be severe since acute application of Aβ1–42 during high frequency stimulation resulted in loss of LTP and diminished autophosphorylation of Ca2+/calmodulin dependent protein kinase II (CaMKII) and CaMKII mediated phosphorylation of GluR1 (Fig. 1) (Zhao et al., 2004). However, PKA activity was not altered by Aβ1–42 application. In neuronal cultures from APP transgenic mice and in wild type neuronal cultures exposed to Aβ1–42 (Almeida et al., 2005) the postsynaptic density scaffolding protein, PSD-95 level was reduced with a concomitant decrease in surface expression of GluR1. In addition synaptophysin levels were also diminished. Interestingly application of Aβ1–40 reduced synaptic PSD-95 levels in a dose dependent manner and this reduction relied on NMDAR activity, Ca2+ influx and cyclin-dependent kinase (cdk5) activity. The surface expression of GluR2 was also decreased in a cdk5 dependent manner following Aβ1–40 application (Roselli et al., 2005). This study suggests that Aβ influences the proteins that assist in insertion and stabilization of AMPARs to postsynaptic membranes.

Fig. 1. Aβ modulates AMPAR surface expression and function. Aβ directly modulates AMPAR channels and alters their kinetics. In addition Aβ promotes caspase mediated cleavage of AMPARs and inhibits autophosphorylation of CaMKII and CaMKII mediated phosphorylation of AMPARs. Aβ induced phosphorylation of GluR2 at S880 aid in receptor endocytosis and Aβ reduces PSD-95 and GluR2 levels in a NMDAR (Ca2+ influx) and cdk 5 dependent manner. Broken arrows indicate inhibitory processes and solid arrows indicate facilitatory processes.

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Acute application of Aβ often results in neurotoxic effects by modulating AMPARs. Such modifications seem to be dependent on the cell type. In avian retinal cell cultures application of a high concentration of Aβ1–42 resulted in excitotoxic cell death which was blocked by AMPAR antagonist DNQX (Louzada et al., 2001). The cultured neuronal cell lines incubated with fibrilar Aβ1–42 resulted in high Ca2+ influx probably through Ca2+ permeable AMPARs as blockade of AMPARs diminished the Ca2+ influx (Blanchard et al., 2004). However, in cultured cerebellar granule cells inhibition of AMPARs elevated toxicity of Aβ25–35 (Allen et al., 1999). The AMPAR mediated excitotoxic cell death observed in these studies may be more attributable to excessive glutamate build up in the synaptic cleft rather than a direct potentiating effect of Aβ on AMPARs. Indeed in AD, excessive glutamate build up has been a well documented proinflammatory pathophysiological condition in which glutamate reuptake mechanisms are impaired. Development of animal models of AD and genetic manipulation of cells to express AD genes (or excess Aβ) resulted in better understanding of mechanisms involved in functional deficits associated with glutamatergic dysfunction. Glutamate receptor dysregulation is found in many animal models of AD. In mice over expressing human APP with Swedish mutation, increased AMPAR binding was observed in the hippocampus at late ages when the Aβ deposits were prominent (Cha et al., 2001). However, recent research reports utilizing transgenic AD animal models strongly suggest that the decline in AMPARs mediated synaptic transmission by Aβ results in synaptic failure. Cultured mouse hippocampal neurons over expressing human wild type APP showed increased Aβ production and reduced excitatory postsynaptic current (EPSC) amplitude indicating a potent reduction in excitatory synaptic transmission. Interestingly, only AMPAR, but not N-methyl-D-aspartate receptor (NMDAR) mediated EPSC was reduced indicating that the amount of glutamate packed per vesicle is not reduced (Ting et al., 2007). In these neurons AMPAR mediated miniature EPSC amplitude and frequency were reduced which suggest complete removal of AMPARs at individual synapses. Results of this report also indicate that the release probability is not altered but only the rate at which reserve pool is refilled, i.e., synaptic vesicle recycling, is modified. This notion is further supported by reduction in dynamin 1, the GTPase that facilitates endocytosis of vesicles, in AD brains (Yao et al., 2003). Reduction in AMPAR mediated miniature EPSC amplitude by Aβ has been demonstrated in other recent studies indicating Aβ induced downregulation of AMPARs in the postsynaptic membranes (Parameshwaran et al., 2007; Townsend et al., 2006). In organotypic slice cultures when APP is over expressed or when Aβ1–42 is exogenously applied, loss of dendritic spines and LTD were observed (Hsieh et al., 2006). Furthermore, in hippocampal slice cultures when Aβ peptides were inducted with lysosomotropic agent chloroquine, expression of AMPAR subunits GluR1 and GluR2/3 was decreased (Bahr et al., 1994) and AMPAR mediated synaptic transmission was compromised (Kanju et al., 2007). Increased Aβ levels obviously lead to reduced synaptic AMPAR expression, increased phosphorylation of GluR2 at S880 and subsequent endocytosis of

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AMPARs, observed in mGluR mediated LTD. Notably this study reported reductions in NMDAR mediated EPSCs which could be explained by loss of dendritic spines. Specific AMPAR downscaling is observed when more than one genetic risk factors are combined. For example in the hippocampus of mice expressing mutated APP and presenilin1, the AMPAR mEPSC amplitude was reduced with morphological observations confirming reduction in synaptic AMPAR numbers (Chang et al., 2006). This finding concluded that hippocampal neurons over expressing APP lead to overload of Aβ resulting in decreased AMPAR numbers by increased removal from postsynaptic membrane and by spine loss. NMDA receptors The N-methyl-D-aspartate receptors are the other major subtype of ligand gated ionotropic glutamate receptors expressed widely in the CNS. Owing to their high Ca2+ permeability, activation of these receptors is often the first event in glutamate induced neuronal injury (Choi, 1995). Accordingly, excitotoxic neuronal death facilitated by excessive glutamate in the synaptic microenvironment and persistent Ca2+ influx through NMDARs is believed to be one of the major causes of neurodegeneration in AD. This is supported by several findings that showed that NMDAR antagonists alleviate neuronal loss (Wenk et al., 2006). In rat magnocellular nucleus basalis, Aβ1–42 and Aβ25–35 induced toxicity was effectively reduced by dizocilpine maleate (MK-801), an NMDAR antagonist. In these neurons Aβ promotes an excitotoxic pathway that includes astroglial depolarization, extracellular glutamate accumulation, NMDAR activation culminating in intracellular Ca2+ overload and cell death (Fig. 2) (Harkany et al., 2000). In addition, direct injection of Aβ1–40 in the hippocampus caused neuronal loss in the CA1 area and NMDA antagonist memantine treatment reduced the neuronal degeneration (Miguel-Hidalgo et al., 2002) supporting the view that NMDARs play a central role in Aβ induced neurotoxicity. An interesting finding worth mentioning here is that mild activation of NMDARs can contribute to elevated synthesis of Aβ. Sublethal activity of NMDARs has been shown to increase Aβ production by increasing a shift from α-secretase to βsecretase activity suggesting that even a mild deregulation of the glutamatergic transmission might increase Aβ overproduction (Lesne et al., 2005). Furthermore, NMDAR function may be required for internalization of Aβ1–42 as in cultured hippocampal slices internalization of Aβ was blocked by selective NMDA receptor antagonists (Bi et al., 2002). Collectively these reports suggest a plausible cyclic neurotoxic process in which initial abnormal NMDAR upregulation favoring Aβ production resulting in excessive glutamate accumulation which further activates NMDARs causing neuronal death. Such forward feeding toxic cycles, if exist and spread through various regions in the brain, might explain the severe neurodegeneration observed as the disease progresses to a more advanced stage. The role of NMDARs in AD pathology could be more than just mediating excitotoxicity. The NMDAR functional downregulation is a strong possibility during the initial stages of the

Fig. 2. Aβ peptide causes disruption of NMDAR function and surface expression through multiple pathways. Aβ promotes influx of Ca2+ through the receptor leading to excitotoxic cell death. Aβ promotes endocytosis of NMDARs, internalization of Aβ, and LTD by mechanisms involving NMDARs. Reduced activity of NMDARs favors Aβ production. Aβ inhibits PKC mediated mGluR activation of NMDARs and GABARs which could result in learning and memory deficits in particular brain regions. Activation of mGluR also reduces Aβ induced apoptosis. Broken arrows indicate inhibitory processes and solid arrows indicate facilitatory processes.

disease when glutamatergic synaptic transmission is believed to be severely compromised. In support of this view many studies have suggested Aβ might reduce surface NMDARs and impair NMDAR function which would depress synaptic glutamatergic transmission. In hippocampal slice cultures a decrease in NMDAR immunopositive pyramidal neurons was observed in the immediate surrounding of Aβ25–35 and Aβ1–40 deposits (Johansson et al., 2006). In cultured hippocampal neurons Aβ1– 42 preconditioning reduced surface expression of the NR1 subunit of NMDARs (Goto et al., 2006) and application of Aβ1– 42 promoted endocytosis of NMDARs in cortical neurons (Snyder et al., 2005). Neurons from AD mouse model showed reduced surface NMDAR numbers and inhibition of γ-secretase restored the surface expression levels of NMDARs (Snyder et al., 2005). These reports suggest the reduction of postsynaptic NMDARs by Aβ. Interestingly altered lipid composition might also have a modulating effect on Aβ induced changes in NMDARs. In transgenic mice over expressing human APP, deficiency in n-3 poly unsaturated fatty acids resulted in profound decreases in NMDAR subunits (NR2A and NR2B) in the cortex and hippocampus, NR1 subunits in the hippocampus and CaMKII in the cortex. Interestingly, these decreases were paralleled by increased caspase activity (Calon et al., 2005). These findings indicate possible inhibitory effects of Aβ on surface NMDAR numbers. In addition to reduced receptor levels, NMDAR functions may also be reduced by Aβ. In a genetic model of AD, application of

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Aβ resulted in a swift and sustained depression of NMDA-evoked currents in cortical neurons (Snyder et al., 2005). In prefrontal cortical neurons, activation of group II metabotropic receptors with (2R,4R)-4-aminopyrrolidine-2,4-dicarboxilate potentiated NMDAR mediated currents through protein kinase C dependent mechanism and Aβ1–42 treatment diminished this potentiation of NMDAR currents. This indicates that Aβ could modify NMDAR function indirectly through other processes (Tyszkiewicz and Yan, 2005). This negative modulation of NMDARs by Aβ might reflect in changes in activity dependent processes like synaptic plasticity. Indeed it has been shown that in the CA1 area Aβ1–42 facilitated the induction of LTD in NMDAR dependent manner (Kim et al., 2001). Therefore, it is possible that at certain crucial time points of this chronic disease Aβ promotes reduction in surface NMDARs and their function. Such reduction would result in diminished glutamatergic transmission and possibly affect plasticity processes in cognitive deficits. Metabotropic glutamate receptors Metabotropic glutamate receptors (mGluRs) belong to a class of G protein linked receptors and have been cloned and classified into three groups according to their second messenger association, sequence homology and agonist selectivity (Pin and Duvoisin, 1995). Group I mGluRs are coupled to phosphoinositide (PI) hydrolysis and intracellular calcium mobilization, whereas group II (mGluR2 and 3) and group III (mGluR4, 6, 7 and 8) are negatively coupled to adenyl cyclase and act as presynaptic autoreceptors (Conn and Pin, 1997; Shigemoto et al., 1997). The mGluRs are located in the presynaptic membrane and regulate glutamate release and thereby optimize synaptic transmission (Coutinho and Knopfel, 2002). Modulation of Aβ involving mGluRs is often through interference of signaling cascades and may entail other receptors. For example, prefrontal cortical neuronal activation of mGluR5 potentiates GABAergic transmission in a PKC dependent manner. Application of Aβ (25–35 and 1–42) abolishes this potentiation. In addition, group II mGluR mediated potentiation of NMDAR currents was also impaired by Aβ1–42. These inhibitory actions of Aβ are probably accomplished by inhibiting mGluR activation of PKC (Tyszkiewicz and Yan, 2005). Since prefrontal cortex is one of the primary brain regions involved in cognitive control (Miller and Cohen, 2001) and GABAregic transmission plays a key role in working memory by shaping temporal flow of information during cognitive operations (Rao et al., 2000), Aβ induced changes in GABAregic and NMDAR functions involving mGluR signaling can cause cognitive deficits. Furthermore, non-amyloidogenic processing is promoted by PKC activation by mGluRs (Lee et al., 1995) and disruption in mGluR activation of PKC might favor Aβ production. Other reports also suggest impairment of mGluR system in different ways and proper mGluR modulation could result in beneficial effects. Stimulation of mGluR5 rescues neuronal cells from Aβ1–40 induced apoptosis (Pizzi et al., 2005) and mGluR agonists may be useful in facilitating synaptic efficacy and treating AD (Lee et al., 1996). Group I mGluR, phos-

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pholipase C signaling is downregulated in the frontal cortex in AD and worsens with the progression of the disease suggesting group I mGluR dysfunction may be involved in the pathogenesis of cognitive impairment in AD (Albasanz et al., 2005). Collectively these reports suggest that mGluR dysfunction is involved in AD pathogenesis. In addition to the well characterized alterations in glutamatergic postsynaptic terminals, reports also suggest that presynaptic functions may be impaired in AD. Early studies have shown that in hippocampal slice cultures, Aβ peptides can be inducted by treatment with lysosomotropic agent chloroquine and in these cultures, levels of presynaptic vesicle glycoprotein synaptophysin were reduced almost to half of the initial level after 6 days of chloroquine treatment (Bahr et al., 1994). Furthermore application of the excitotoxin, kainic acid, amplified the reductions in synaptophysin levels caused by chloroquine (Bahr et al., 1994) suggesting that prevalence of excitotoxic conditions could aggravate mechanisms of synaptic decline in AD. In the hippocampus of transgenic AD mice a possible downregulation of presynaptic calcineurin in the mossy fiber terminals may contribute to dysregulation of glutamate release (Celsi et al., 2007). Though some studies suggest that acute application of Aβ may not affect presynaptic vesicle release (Ting et al., 2007; Townsend et al., 2006) other reports strongly suggest reduced levels of synaptophysin in postmortem AD brains (Szegedi et al., 2005) and in experimental models of AD (Bahr et al., 1998; Bendiske and Bahr, 2003; Mucke et al., 2000). Additionally, presynaptic vesicle cycling (Ting et al., 2007) and even glutamate release (Parameshwaran et al., 2007) have been shown to be reduced by Aβ. The extent of synaptic pathology induced by Aβ may be further understood by observations that show these peptides are selectively taken up by cells that are vulnerable and are at risk in AD (Bahr et al., 1998). Furthermore, Aβ peptides selectively accumulate in preand postsynaptic compartments in transgenic mouse models and in human AD brains (Takahashi et al., 2002). Concluding remarks AD is an age related disease in which initial mild cognitive deficits progress unabated. Cognitive deficits are paralleled by accumulation of Aβ and neurofibrillary tangles. Initial AD is believed to be a pathological condition involving synaptic dysfunction. In particular, glutamatergic synaptic function seems to be affected in major brain areas involved in learning and memory; changes in presynaptic components (function) might affect glutamate release during activity dependent processes like synaptic plasticity and postsynaptic sites show marked reduction in surface receptor number and function. In addition, scaffold proteins that anchor glutamate receptors are also downregulated in AD. Several research reports in the recent past have strongly suggested that AMPA, NMDA and metabotropic glutamate receptors may play crucial roles in AD pathogenesis. Therefore, given the initial onset of deficits in glutamatergic synaptic transmission and their role in later excitotoxic cascades, targeting these receptors for AD therapy might prove to be beneficial.

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