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NeuroAids Vol. 3, Issue 6 (November 2000)           

The NMDA Receptor - Its Role in Neuronal Apoptosis and HIV-Associated Dementia

M. Kaul1, S. A. Lipton1

1Center for Neuroscience and Aging, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037 USA

E-mail: mkaul@burnham-inst.org, slipton@burnham-inst.org .

Keywords: Glutamate receptors, NMDA receptor, excitotoxicity, neurotoxicity, neuronal death, neuronal apoptosis, neurodegeneration, HIV-1-associated dementia, HIV-1, AIDS, chemokine receptors, macrophages, microglia

Acknowledgments: This work was supported in part by NIH grants P01 HD29587 and R01 EY09024 (to S.A.L.) and by fellowships from the DFG and American Foundation for AIDS Research (to M.K.). We thank several present and former members of the Lipton laboratory who contributed to the work described herein, including Drs. Evan Dreyer, Peter Kaiser, Michael Yeh, Samantha Budd, Gwenn Garden, and Yun-Beom Choi, as well as members of the collaborating laboratories of Drs. Jonathan Stamler, Howard Gendelman, Pierluigi Nicotera and Sten Orrenius.


Abstract
Abstract Introduction Glutamate receptors, excitotoxicity and neuronal cell death HIV-1 infection and NMDA receptor-related neuronal apoptosis Conclusions References

The N-methyl-D-aspartate receptor (NMDAR) is a highly Ca2+-permeable, ligand-gated ion channel in neurons and a member of the ionotropic glutamate receptor family. Excessive stimulation of the NMDAR leads to excessive intracellular Ca2+ influx, generation of free radicals such as nitric oxide and reactive oxygen species, collapse of the mitochondrial membrane potential, loss of ATP, and eventually neuronal apoptosis or necrosis depending on the intensity of the initial insult and the extent of energy recovery. This process is termed excitotoxicity and appears to be an integral component in a final common pathway to neuronal injury in neurodegenerative disorders including HIV-associated dementia. Infection by HIV-1 is mediated by interaction of the virus' envelope protein, gp120, with chemokine receptors in addition to CD4. These HIV co-receptors are expressed on all cell types in the CNS, although microglia are the predominant if not the sole cell type that is productively infected. HIV-associated neuronal damage occurs predominantly via an indirect pathway that involves the release of various excitotoxins by macrophages. Both NMDAR antagonists and specific chemokines can protect neuron, at least in vitro, against apoptosis induced by HIV/gp120 or by NMDA, suggesting cross-talk in the signaling pathways triggered by chemokine and NMDA receptors. The present review discusses neuronal apoptosis and HIV-associated dementia in light of recent findings concerning NMDARs and chemokine receptors.

Introduction
Abstract Introduction Glutamate receptors, excitotoxicity and neuronal cell death HIV-1 infection and NMDA receptor-related neuronal apoptosis Conclusions References

Neuronal injury and apoptosis may account, at least in part, for neurological complications associated with HIV-1 infection ranging from mild cognitive and motor impairment to dementia. The primary cell types infected in the brain are macrophages and microglia. These cells have been found in vivo and in vitro to release neurotoxic factors. Evidence has accumulated that neuronal apoptosis in HIV-related insults occurs predominantly via an indirect pathway comprising a complex cooperation of cytokines, reactive oxygen and nitrogen species, lipid mediators and excitotoxins. These molecules lead to excessive stimulation of the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR). Of note, chemokine receptors, which in conjunction with CD4 mediate HIV infection of macrophages/microglia, are present on neurons and astrocytes in addition to macrophages/microglia. Thus, these receptors potentially allow direct interaction between the virus and neurons (Fig. 1).

Figure 1

Figure 1 (Enlarge): Current model of NMDA receptor-associated neuronal injury. Schematic illustration of the NMDAR-related signaling pathways that lead to neuronal apoptosis and may contribute to neurodegenerative disease, including HIV-associated dementia. These pathways can be targeted to prevent neuronal apoptosis and thus may help treat various neurologic diseases. Drug or molecular therapies are being developed to (1) antagonize NMDA receptors (NMDA-Rc), (2) modulate activation of the p38 mitogen activated kinase (MAPK) - MEF2C (transcription factor) pathway, (3) prevent toxic reactions of free radicals such as nitric oxide (NO) and reactive oxygen species (ROS), and (4) inhibit apoptosis-inducing factors including caspases. Activation of the p38 MAPK - MEF2C pathway appears to occur upstream of the effector caspases (not illustrated here).

The fact that specific chemokines ameliorate HIV/gp120-induced neuronal apoptosis that is mediated by NMDARs suggests a functional connection between the receptors for chemokines and NMDA. Accordingly, here we review the role of the NMDAR in HIV-1-related and excitotoxic neuronal cell death.


Glutamate receptors, excitotoxicity and neuronal cell death
Abstract Introduction Glutamate receptors, excitotoxicity and neuronal cell death HIV-1 infection and NMDA receptor-related neuronal apoptosis Conclusions

References

 

The NMDAR belongs to a large and heterogeneous family of membrane proteins, the glutamate receptors. These glutamate receptors recognize the major excitatory neurotransmitter in the central nervous system (CNS), (S)-glutamic acid (Glu), and other related excitatory amino acids (EAAs) (1)(2)(3). To date, four classes of EAA receptors have been identified and many member subunits cloned. These include three "ionotropic" receptor classes [iGluRs, comprised of ligand-gated ion channels termed (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid (AMPA), kainic acid (KA) and NMDA receptors], and one G-protein coupled or "metabotropic" EAA receptor class [mGluRs] (1)(2)(4). Both, iGluRs and mGluRs are considered to play important roles in the CNS under normal physiologic and pathophysiologic conditions. Under physiological conditions, activation of iGluRs in neurons initiates transient depolarization and excitation. AMPARs mediate the fast component of excitatory postsynaptic currents, and NMDARs underlie a slower component. Presynaptic release of Glu and consequent depolarization of the postsynaptic neuronal membrane via AMPAR-coupled channels relieve the Mg2+ block of the ion channel associated with the NMDAR under resting conditions. This effect allows subsequent controlled Ca2+ influx through the NMDAR-coupled ion channel. This voltage-dependent modulation of the NMDAR results in activity-driven synaptic modulation (2)(5). However, extended and/or excessive NMDAR activation and consequent overexcitation can damage a neuron and eventually cause its death. This process is called excitotoxicity and appears to be favored by sustained elevation of the intracellular Ca2+ concentration and/or compromised cellular energy metabolism (5)(6).

A role for Glu excitotoxicity in brain disorders was first suggested by the work of Olney following the pioneering work of Lucas and Newhouse in the retina (6). Subsequently, several lines of evidence indicated that excessive stimulation of glutamate receptors contributes to the neuropathological processes in stroke, head and spinal cord injury, Huntington's disease, Parkinson's disease, possibly Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma and HIV-1 associated dementia (1)(5)(7). Indeed, excitotoxicity seems to represent a common final pathway in a wide variety of neurodegenerative disorders (8).

The NMDAR has attracted particular interest as a major player in excitotoxicity because this receptor, in contrast to most non-NMDARs (AMPA and KA receptors), is highly permeable to permeable to Ca2+, and excessive Ca2+ influx can trigger excitotoxic neuronal injury (3)(9). In addition, NMDAR antagonists effectively prevent glutamate neurotoxicity, both in vitro and in vivo in animal studies, as well as in recent phase III clinical trials with the NMDAR open-channel blocker, memantine (2)(5)(10). However, AMPA and KA receptors can also mediate excitotoxicity and contribute to neuronal damage under certain conditions (2)(5). For example, a subpopulation of Ca2+ or Zn2+-permeable AMPA receptor-coupled channels has been implicated in selective neurodegenerative disorders such as ischemia, epilepsy, Alzheimer's disease, and amyotrophic lateral sclerosis (3). Also transgenic mice overexpressing AMPARs display increased damage subsequent to ischemia when compared to control animals (11).

Excessive stimulation of the NMDAR induces several detrimental intracellular signals that contribute to neuronal cell death by apoptosis or necrosis, depending on the intensity of the initial insult (12). Excessive Ca2+ influx through NMDAR-coupled ion channels leads to an elevation of the intracellular free Ca2+ concentration to a point that results in Ca2+ overload of mitochondria, depolarization of the mitochondrial membrane potential and a decrease in ATP synthesis. Additionally, excessive intracellular Ca2+ stimulates protein kinase cascades and the generation of free radicals, including reactive oxygen species (ROS) and nitric oxide (NO) (12). NO can react with ROS to form cytotoxic peroxynitrite (OONO-) (12), and in alternative redox states, NO can also activate p21ras by S-nitrosylation (transfer of the NO group to a critical cysteine thiol) (13). However, the NO group can also inhibit caspases in cerebrocortical neurons via S-nitrosylation, thereby attenuating apoptosis (16). The scaffolding protein PSD-95 (postsynaptic density-95) links the principal subunit of the NMDAR (NR1) with neuronal nitric oxide synthase (nNOS), a Ca2+-activated enzyme, and thus brings nNOS into close proximity to Ca2+ via the NMDAR-operated ion channel (14). Importantly, excessive Ca2+ influx also activates the stress-related p38 mitogen-activated protein kinase (p38 MAPK)/myocyte enhancer factor 2C (MEF2C transcription factor) pathway and c-Jun N-terminal kinase (JNK) pathways in cerebrocortical or hippocampal neurons. Activation of these pathways has been implicated in neuronal apoptosis (15)(17).

As stated above, excessive intracellular Ca2+ accumulation after NMDAR stimulation leads to depolarization of the mitochondrial membrane potential (DYm) and a drop in the cellular ATP concentration. If the initial excitotoxic insult is fulminant, the cells do not recover their ATP levels and die at this point because of the loss of ionic homeostasis, resulting in acute swelling and lysis (necrosis). If the insult is more mild, ATP levels recover, and the cells enter a delayed death pathway requiring energy, known as apoptosis (12).

It has been reported that NMDAR-mediated excitotoxicity leading to neuronal apoptosis also involves activation of the Ca2+/calmodulin-regulated protein phosphatase calcineurin (12), release of cytochrome c from mitochondria (18), activation of caspase-3 (19), lipid peroxidation (19), and cytoskeletal breakdown (12). Inhibition of calcineurin and caspase-3 with FK506 and caspase inhibitors, respectively, can attenuate this form of excitotoxicity (12)(19). It has been proposed that the adenine nucleotide translocator (ANT) is a part of the mitochondrial permeability transition pore (PTP) and participates in mitochondrial depolarization. Indeed, our group has found that pharmacologic blockade of the ANT with bongkrekic acid prevented collapse of the mitochondrial membrane potential (DYm), as well as subsequent caspase-3 activation and NMDA-induced neuronal apoptosis. However, treatment with bongkrekic acid failed to inhibit the transient drop in ATP concentration (although it hastened the recovery of ATP levels) and did not prevent the liberation of cytochrome c into the cytosol. Thus, initiation of caspase-3 activation and resultant neuronal apoptosis after NMDAR activation require a factor(s) in addition to cytochrome c release (18).

Interestingly, stimulation of specific subtypes of the G protein-coupled mGluRs interferes with excitotoxic NMDAR-mediated activation of MAPKs and can attenuate subsequent neuronal cell death (15). Additionally, glial cells, including astrocytes, microglia and oligodendrocytes, may possess glutamate receptors (4). Both AMPA and KA receptor subtypes and mGluRs have been reported on microglia, and functional NMDARs have been reported to exist in some cases on astrocytes and oligodendrocytes. Glial glutamate receptors appear to be involved in interactions between neuronal and glial cells, and hence may conceivably contribute to synaptic efficacy. Furthermore, under certain pathologic circumstances, such as cerebral hypoxia-ischemia and possibly HIV-1 infection of the brain, astrocytes and oligodendrocytes may undergo glutamate-mediated excitotoxic cell death (4).

 


HIV-1 infection and NMDA receptor-related neuronal apoptosis
Abstract Introduction Glutamate receptors, excitotoxicity and neuronal cell death HIV-1 infection and NMDA receptor-related neuronal apoptosis Conclusions References

HIV-associated dementia eventually develops in approximately half of children and a quarter of adults infected with HIV-1 (7). Neuropathological features that may accompany this cognitive-motor complex include dendritic and synaptic damage, apoptosis and frank loss of neurons, myelin pallor, astrocytosis, and infiltration of macrophages, microglia and multinucleated giant cells (7)(20)(21).

Macrophages and microglia play a crucial role in HIV-associated dementia because they are the predominant cells productively infected with HIV-1 in AIDS brains (7), although infection of astrocytes has also been rarely observed in pediatric cases (22). Also, several lines of evidence suggest that HIV-1 infected macrophages migrate into the brain (23), and the presence of macrophages/microglia has been reported to correlate with the severity of HIV-associated dementia (24). Furthermore, we and our colleagues have shown that HIV-1 infected or immune stimulated macrophages/microglia produce neurotoxins (7)(25).

The mechanisms that initiate HIV-associated dementia are not completely understood. HIV-1 apparently enters the CNS soon after peripheral infection, and the virus primarily resides in microglia and macrophages, especially in those located in the perivascular space (23). It is not clear if the migration of infected monocytes and macrophages represents the only pathway for viral entry into the brain. Additionally, infection of monocytoid cells per se may not be sufficient to initiate the dementing process (23). In the CNS, HIV-1 is thought to cause immune activation of macrophages/microglia, changes in statement of cytokines, chemokines and their receptors, and up-regulation of endothelial adhesion molecules (23). However, these observations may be the result of the process rather than the inciting event for HIV-1-associated brain pathology. Therefore, it has been proposed that peripheral (non-HIV) infection or other factors may trigger events leading to dementia after HIV-1 infection in the CNS has been established. One such factor could be the increased number of activated monocytes in the circulation that express CD16 and CD69. These activated cells could possibly adhere to the normal endothelium of the brain microvasculature, transmigrate, and then trigger a number of deleterious processes (23).

Infection of cells by HIV-1 can occur after binding of the viral envelope protein gp120 to one of several possible chemokine receptors in conjunction with CD4. Depending on the exact type of gp120, different HIV-1 strains may use CXCR4 (26), CCR3, CCR2, CCR5, or a combination of these chemokine receptors to enter target cells (27). Microglia are infected by HIV-1 primarily via CCR3 and CCR5 (28). CCR5 and CXCR4, among other chemokine receptors, are also present on neurons and astrocytes, and, in particular CXCR4 and CCR3 are highly expressed on neurons of macaques and humans (29). In vitro studies strongly suggest that chemokine receptors are directly involved in HIV-associated neuronal damage (17)(30)(31).

Even in the absence of intact virus, the HIV proteins gp120, gp41, gp160, Tat, Nef, Rev, and Vpr have been reported to initiate neuronal damage both in vitro and in vivo (32)(33)(34)(35)(36). In this regard, the viral envelope protein gp120 has been of particular interest as it is essential for selective binding and signaling of HIV-1 to its target cell and for viral infection (17)(28)(30)(31)(34). Additionally, evidence has been provided that gp41, the membrane-spanning region of the viral envelope protein, correlates with the statement of immunologic/type II NOS (iNOS) as well as the degree of HIV-associated dementia (35).

A recurring question has been whether HIV-1 or its component proteins induce neuronal damage predominantly by an indirect route, e.g., via toxins produced by infected or immune-stimulated macrophages and/or astrocytes, or by a direct route, e.g., via binding to neuronal receptors (7)(17)(37). Several lines of evidence suggest that HIV-associated neuronal injury involves predominantly an indirect route and resulting excessive activation of NMDARs with consequent excitotoxicity (25)(38)(39). Analysis of specimens from AIDS patients (39) as well as in vivo and in vitro experiments indicate that HIV-1 infection create excitotoxic conditions, most probable indirectly via induction of soluble factors in macrophage/microglia and/or astrocytes, such as glutamate-like molecules, viral proteins, cytokines, chemokines, and arachidonic acid metabolites (7)(37)(40). However, it has been suggested that HIV-1 or its protein components can directly interact with neurons and modulate NMDAR function, at least under some conditions (30)(41).

Picomolar concentrations of soluble HIV/gp120 induce by in vitro and in vivo injury and apoptosis in primary rodent and human neurons (32)(34). Additionally, our group and subsequently several others have shown that gp120 contributes to NMDAR-mediated neurotoxicity (38). Both voltage-gated Ca2+ channel blockers and NMDAR antagonists can ameliorate gp120-induced neuronal cell death in vitro (38)(42). Transgenic mice expressing gp120 manifest neuropathological features that are similar to the findings in brains of AIDS patients, and in these mice neuronal damage is ameliorated by the NMDAR antagonist memantine (33)(43). It is also conceivable that other glutamate receptors in addition to NMDARs influence HIV-associated neuronal damage. In particular, disparate mGlurs have been found to up-or down-modulate excitotoxic signals triggered by NMDARs (15).

In our hands, the predominant mode of neurotoxicity of HIV-1 or gp120 to cerebrocortical neurons requires the presence of macrophages/microglia; HIV-1 infected or gp120 stimulated mononuclear phagocytes have been shown to release neurotoxins that directly stimulate the NMDAR (17)(25). Those macrophage toxic factors include molecules that directly or indirectly act as NMDAR agonists, such as quinolinic acid, cysteine, platelet-activating factor (PAF), and a low-molecular weight compound named NTox (7)(40)(44). Additionally, activated macrophages/microglia and possibly astrocytes produce inflammatory cytokines, including TNF-a and IL-1b, arachidonic acid metabolites, and free radicals (ROS and NO) that may indirectly contribute to excitotoxic neuronal damage (7)(40). TNF-a and IL-1 b may amplify neurotoxin production by stimulating adjacent glial cells and by increasing iNOS activity (40)( Fig. 2).

Figure 2

Figure 2 (Enlarge): Current model of HIV-associated neuronal injury. Immune activated- and HIV-infected brain macrophages/microglia release potentially neurotoxic substances. These substances from macrophages and also possibly from reactive astrocytes contribute to neuronal injury and apoptosis as well as to astrocytosis. A major pathway of entry of HIV-1 into monocytoid cells is via gp120 binding, and therefore it is not surprising that gp120 (or a fragment thereof) is capable of activating uninfected macrophages to release similar factors to those secreted in response to frank HIV infection. Macrophages bear CCR5 and possibly CXCR4 chemokine receptors on their surface in addition to CD4, and gp120 binds via these receptors. Some populations of neurons and astrocytes have been reported to also bear CXCR4 and CCR5 receptors on their surface, raising the possibility of direct interaction with gp120. Macrophages and astrocytes have mutual feed-back loops (signified by the reciprocal arrows). Cytokines participate in this cellular network in several ways. For example, HIV-infection or gp120-stimulation of macrophages enhances their production of TNF-a and IL-1b (solid arrow). The TNF-a and IL-1b produced by macrophages stimulate astrocytosis. Neuronal injury is primarily mediated by overactivation of NMDARs with a resultant excessive increase in intracellular Ca2+ levels. This in turn leads to overactivation of a variety of potentially harmful enzyme systems, the formation of free radicals, and release of the neurotransmitter glutamate. Glutamate subsequently overstimulates NMDARs on neighboring neurons, resulting in further injury. This final common pathway of neurotoxic action can be blocked by NMDAR antagonists. For certain neurons, depending on their exact repertoire of ionic channels, this form of damage can also be ameliorated to some degree by calcium channel antagonists or non-NMDAR antagonists. Additionally, agonists of b-chemokine receptors, which are present in the CNS on neurons, astrocytes and microglia, can confer partial protection against neuronal apoptosis induced by HIV/gp120 or NMDA. IFN, interferon; IL interleukin; NO., nitric oxide; O2.-, superoxide anion; TNF tumor necrosis factor.

 

In contrast to these indirect neurotoxic pathways, it has been reported that gp120 can directly interact with neurons in the absence of glial cells. Recently, gp120 was found to act at chemokine receptors directly on neurons to induce their death (30). Additionally, nanomolar concentrations of gp120 have been reported to interact with the glycine binding site of the NMDAR (45). Furthermore, gp120 may produce a direct excitotoxic influence via NMDAR-mediated Ca2+ oscillations in rat hippocampal neurons (46), and may bind to noradrenergic axon terminals in neocortex, where it possibly potentiates NMDA-evoked noradrenaline release (47). Nonetheless, many if not all of these direct effects on neurons were observed in vitro in the absence of glial cells. Since glial cells are known to modify these death pathways, we feel that under in vivo conditions, the indirect route to neuronal injury is the predominant one.

Along these lines, gp120 has been found to aggravate excitotoxic conditions by impairing astrocyte uptake of glutamate via arachidonic acid that is released from activated macrophages/microglia (37). Metabolites of arachidonic acid, such as prostaglandins, also stimulate a Ca2+-dependent release of Glu by astrocytes (48). Moreover, HIV-1 can induce astrocytic statement of the b-chemokine known as macrophage chemotactic protein-1 (MCP-1). This b-chemokine in turn attracts additional mononuclear phagocytes and microglia to further enhance the potential for indirect neuronal injury via the release of macrophage toxins (49).

HIV-1 infection and its associated neurological dysfunction involve both chemokine receptors and NMDAR-mediated excitotoxicity. This dual receptor involvement raises the question whether the G protein-coupled chemokine receptors and ionotropic glutamate receptors might influence each other's performance. Indeed, the b-chemokine known as "regulated upon activation T cell expressed and secreted" (RANTES), which binds to the chemokine receptors CCR1, CCR3 and CCR5, can abrogate neurotoxicity induced by gp120 (17) or by excessive NMDAR stimulation (50). In turn, excitotoxic stimulation can enhance expression of CCR5 (51). Whether or not these findings reflect a mechanism of feedback or crosstalk of these receptors within the brain remains to be elucidated.



Conclusions
Abstract Introduction

Glutamate receptors, excitotoxicity and neuronal cell death

 

 HIV-1 infection and NMDA receptor-related neuronal apoptosis Conclusions References

Progress has been made in understanding the mechanisms of toxicity associated with overstimulation of NMDARs that leads to pathological neuronal excitation, excessive Ca2+ influx, and apoptosis. Increasing evidence indicates that excitotoxicity represents a common final pathway in neurological disorders, including HIV-associated dementia. NMDAR antagonists can inhibit both in vitro and in vivo the neurotoxicity of HIV/gp120 and of glutamate. Additionally, chemokine receptors, essential co-mediators of HIV infection, are present in the CNS on neurons, astrocytes and microglia, and can in part also confer protection against neuronal apoptosis induced by HIV/gp120 or NMDA. These findings suggest a functional connection between receptors for chemokines and NMDA. Recently, phase III trials with the NMDAR antagonist memantine have demonstrated benefit in a series of neurodegenerative conditions, including Alzheimer's disease and Vascular dementia. A large, multi-center clinical trial of memantine for HIV-associated dementia is currently being analyzed. In the future, clinical studies may lead to therapeutic applications of chemokines for neurodegenerative disorders as well.


References
Abstract Introduction Glutamate receptors, excitotoxicity and neuronal cell death

HIV-1 infection and NMDA receptor-related neuronal apoptosis

 

 Conclusions References

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