What Role Does Glutamate Play in the Development of Different Neurodegenerative Diseases, and can the Glutamate Signalling System be a Target for Therapeutic Treatments?

Image author: ColiN00B, Pixabay

Written by: Alexander Xiang

Introduction 

Neurodegenerative diseases are a class of illnesses characterized by a progressive loss of vulnerable groups of neurons.1 These diseases, which include conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) are one of the most common causes of morbidity and cognitive impairment in older adults, affecting 15 million individuals worldwide.2 

While the prevalence of such conditions is widespread and their pathologies are well-documented, treatments have lagged behind, often improving quality of life instead of slowing the progression of the disease itself. Nevertheless, the lack of effective treatments is not a result of a lack of research, as there has been a litany of investigation into potential treatments, ranging from receptor antagonists to medications that result in the fortification of transcortical networks.3 One of the most promising approaches elucidated by research examining the symptoms and progression of neurodegenerative diseases is the glutamate signalling system, the most common excitatory neurotransmitter in the central nervous system (CNS).4 

The following review will examine the glutamate signalling system, its role in two of the most common neurodegenerative diseases (Alzheimer’s and Parkinson’s disease), as well as evaluating the glutamate signalling system as a target for therapeutic treatments. 

Glutamate and Neurodegenerative Disease Background 

L-glutamate, also known as glutamate, is the principal excitatory neurotransmitter within the vertebrate CNS. Its receptors are classified into two major divisions, ionotropic (iGluR) and metabotropic (mGluR), due to their selective affinity for specific agonists.5,6 Each subtype of these metabotropic receptors are specialized to specific regions of the brain with different types of cells in the nervous system, such as astrocytes and oligodendrocytes, expressing different forms of the mGluR receptor.7 

While glutamate is vital for normal bodily functions, its overuse can lead to a phenomenon known as excitotoxicity, whereby prolonged glutamate receptor activation leads to chronically elevated intracellular calcium levels, leading to neuronal damage and cell death.8 It is this form of toxicity that is common in the early stages of AD, as damage to basal forebrain (BF) neurons has been regarded as one of the most reliable indicators of early stage Alzheimer’s.9,10 

Although somewhat similar, Parkinson’s disease has a different pathology compared to that of Alzheimer’s disease, and is characterized by the degradation of dopaminergic neurons in specific regions of the brain.11 While the degradation of dopaminergic neurons would appear separate to the glutamate signalling system, it is crucial to be cognizant of the pleiotropic effects of glutamate, as it also plays a role of neuroprotection and promoting cell cycle progression.11 

Assessment of Current Research 

The existing body of literature examining the connections between the glutamate signalling system and its role in AD is relatively straightforward. Studies by Snyder et al. have indicated that human AD brains express fewer N-methyl-D-aspartate (NMDA) receptors, a specific subtype of ionotropic glutamate receptor, compared to healthy controls.12 This discrepancy has been attributed to the presence of β-amyloid plaques, which promote endocytosis of these receptors. Moreover, studies by both Danysz et al. and Revett et al. have demonstrated that these β-amyloid plaques not only decrease expression of glutamate transporters such as vesicular glutamate transporter (VGluT) but also inhibit other glutamate recycling pathways that terminate excitatory stimuli.13,14 

Additionally, the aforementioned investigations by Danysz et al. also demonstrated that β-amyloid plaques can modulate the electrophysiological functions of NMDA receptors.14 These aforementioned alterations result in a phenomenon known as “long term depression” (LTD), which is associated with the synapse loss commonly observed in the vast majority of AD cases.15 Finally, investigations by Wu et al. have implicated β-amyloid plaques in the augmented production of NMDA coagonists, molecules that are required to be bound alongside glutamate to achieve NMDA receptor activation.16 Cultured microglial cells exposed to β-amyloid plaques were observed to have elevated levels of common NMDA coagonists, such as D-serine.16 

Similarly to AD, the glutamate signalling system plays a crucial role in the onset and progression of PD, though the specific connection is not as clear. Glutamate is largely responsible for the onset of common Parkinson’s-related motor symptoms, as the degradation of dopaminergic neurons has been shown to lead to increased glutaminergic activity in the subthalamic nucleus (STN).6 Furthermore, similar to AD, glutamate levels are significantly elevated in PD patients, contributing to the eventual degradation of dopaminergic neurons in the nervous system. Finally, studies by Guo et al. have implicated NMDA receptors in the pathology of PD, as glutamate activation of NMDA receptors is shown to be substantially higher in experimental PD models and PD patients compared to those of controls.17 

Assessment of Potential Therapeutic Treatments 

Given the intricate connections between the glutamate signalling system and AD, it is understandable that a considerable amount of research into therapeutics has been focused on this specific avenue, yielding mixed results. Memantine, the only federally approved drug for the treatment of Alzheimer’s disease that is not a cholinesterase inhibitor, was developed based on the role NMDA receptors play in the loss of synapses in many AD patients.18 The function of memantine is to block current flow through the channels of NMDA receptors, known as open channel blockers, leading to a reduction in excitotoxic effects.18 

Nevertheless, the development of alternative, stronger NMDA receptor antagonists, such as ketamine, have failed, due to the key role of NMDA receptors in synaptic communication and memory formation.19 The success of memantine is largely a result of both its low affinity for the NMDA receptor, as well as its action as an open channel blocker, mitigating the overstimulation of NMDA receptors while simultaneously maintaining its crucial function.19 

Alternative research techniques have examined treatments that target the glutamate signalling system, such as regulating astrocytic glutamate transporters responsible for glutamate uptake and termination.20 For instance, studies by Pajarillo et al. have identified significant correlations between glutamate transporter efficacy and progression of Alzheimer’s disease.20 Further follow-up studies performed by Mutkus et al. identified the potential use of several pharmacological agents, including growth factors and histone deacetylase inhibitors, in enhancing the efficacy of glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1).21 However, the current research examining this particular avenue for treatment has remained in preclinical stages, indicating further investigations are necessary. 

In contrast, treatments for Parkinson’s disease have been focused on administration of L-DOPA, a signalling molecule that alleviates the symptoms of Parkison’s disease through the reestablishment of basal dopamine levels in the striatum.6 However, L-DOPA administration also leads to harmful side effects, known as L-DOPA induced dyskinesia (LID).22 The glutamate signalling system remains imperative in the mitigation of harmful side-effects, as studies by Rylander et al. have indicated that the development of LID is largely because of an imbalance between glutamate and dopamine signalling.22

In terms of treatment for Parkinson’s disease itself, investigations by Paoletti et al. identified that antagonism of ionotropic glutamate receptors is effective, however the debilitating side-effects mean that treatment would be clinically unfeasible.23Investigations into metabotropic glutamate receptors have also been inconclusive, as studies Rylander et al. using animal models illustrated that negative allosteric modulators of Group I glutamate receptors are ineffective in the treatment of both Parkinson’s symptoms and LID side-effects.22 However, modulation of other subtypes of mGLuR have proved promising, as studies by both Ossowska et al. and Phillips et al. illustrated that antagonism of type 5 glutamate receptors, using a compound known as MPEP, mitigates motor deficits in rat models.24,25 

Critiques of Current Research 

Although each of the studies examined for this critical review have their individual strengths and limitations, a holistic examination of the studies consulted for this review reveal several overarching themes that affect the applicability of the conclusions drawn from each study. Firstly, one of the benefits of the current research in this particular field is the reliance on systematic reviews that examine the results of several studies in order to draw conclusions.4,6,8,11 For instance, one particular review conducted by Ribero et al. drew on the results of over a dozen investigations when examining the role of Group I mGluRs on Parkison’s disease.4 

Nevertheless, one consistent limitation of the research examined for this critical review is the lack of studies that corroborate these conclusions in phase I-III trials. The vast majority of investigations in this field rely on animal models, such as monkeys and rats, to draw their conclusions.22 While this may be necessary due to the ethical and financial limitations of conducting phase I-III trials, human trials must be conducted to accurately develop pharmacological agents that mitigate the side-effects of AD and PD in vivo

Finally, another limitation of the studies investigated for this critical review is the absence of multi-dimensional studies that examine the role of several neurotransmitters on the progression and diagnosis of AD and PD. While investigations studying glutamate are useful, neurodegenerative diseases such as AD and PD are maladies that attack several different nervous system signalling pathways. Consequently, in order to develop treatments that are able to slow or stop the progression of AD and PD entirely, researchers must account for the effects of these treatments on multiple nervous system signalling systems. For instance, while antagonism of glutamate receptors appears to be a promising avenue to reduce the effects of PD, it may not attenuate the effects of PD on the dopamine signalling system, such as the degradation of dopaminergic neurons.

Conclusion 

Recent investigations and systematic analyses have demonstrated the effects of both AD and PD on the glutamate signalling system, promoting excitotoxicity which eventually leads to neuronal cell death, commonly observed in the early stages of these disorders.9,11 Furthermore, follow-up studies have established potential avenues for treatment, such as NMDA receptor antagonists, GLAST and GLT-1 modifiers, as well as allosteric modulators of metabotropic glutamate receptors. 

Although the prevailing research surrounding the glutamate signalling system has established important connections between the glutamate signalling system and the development of both Alzheimer’s and Parkinson’s disease, there remain limitations surrounding current research that necessitates further investigations before these conclusions can be applied in a clinical setting. The vast majority of these investigations rely on animal models in order to evaluate treatment efficacy, due to concerns surrounding the side-effects of these pharmacological agents. Additionally, many of the studies examined in this review fail to consider the effects of potential treatments on other related signalling systems present in the nervous system. 

Future investigations should target two specific avenues. The first is to increase the number of trials that incorporate human subjects in order to determine the potential discrepancies in treatment efficacy between human and animal models. The second avenue is to take a multidimensional approach and examine potential treatments that are able to target multiple signalling systems, not just the glutamate signalling system.

References 

1. Dugger NB, Dickson WD. Pathology of Neurodegenerative Diseases. Cold Spring Harb Perspect Biol. 2017;9(7):1-22. Available from: doi:10.1101/cshperspect.a028035.

2. Erkinnen GM, Kim M, Geschwind DM. Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases. Cold Spring Harb Perspect Biol. 2018;10(4):1-44. Available from: doi:10.1101/cshperspect.a033118. 

3. Weller J, Budson A. Current Understanding of Alzheimer’s Disease Diagnosis and Treatment. F1000Res. 2018;31(7):1-9. Available from: doi:10.12688/f1000research.14506.1. 

4. Ribeiro MF, Vieira BL, Pires GWR, Olmo PR, Ferguson SGS. Metabotropic Glutamate Receptors and Neurodegenerative Diseases. Pharmacol Res. 2017;115:179-191. Available from: doi:10.1016/j.phrs.2016.11.013. 

5. Nakanishi S. Metabotropic glutamate receptors: Synaptic transmission, modulation, and plasticity. Neuron. 1994;13(5): 1031-1037. Available from: doi:https://doi.org/10.1016/0896-6273(94)90043-4. 

6. Crupi R, Impellizzeri D, Cuzzocrea S. Role of Metabotropic Glutamate Receptors in Neurological Disorders. Front Mol Neurosci. 2019;8(12):1-11. Available from: doi:10.3389/fnmol.2019.00020. 

7. D’Antoni S, Beretta A, Bonaccorso MC, Bruno V, Aronica E, Nicoletti F, et al. Metabotropic Glutamate Receptors in Glial Cells. Neurochem Res. 2008;33(12):2436-43. Available from: doi:10.1007/s11064-008-9694-9.

8. Doble A. The Role of Excitotoxicity in Neurodegenerative Disease: Implications for Therapy. Pharmacology and Therapeutics. 1999;81(3):163-221. Available from: doi:https://doi.org/10.1016/S0163-7258(98)00042-4. 

9. Winkler J, Thal LJ, Gage HF, Fisher JL. Cholinergic Strategies for Alzheimer’s Disease. J Mol Med (Berl). 1998;76(8):555-67. Available from: doi:10.1007/s001090050250.

10. Gu Z, Cheng J, Zhong P, Qin L, Liu W, Yan Z. Aβ selectively impairs mGluR7 modulation of NMDA signaling in basal forebrain cholinergic neurons: implication in Alzheimer’s disease. J Neurosci. 2014;34(41):13614-28. Available from: doi:10.1523/JNEUROSCI.1204-14.2014. 

11. Zhang Z, Zhang S, Fu P, Zhang Z, Lin K, Ko KJ, et al. Role of Glutamate Receptors in Parkinson’s Disease. Int J Mol Sci. 2019;20(18):4391. Available from: doi:10.3390/ijms20184391. 

12. Snyder ME, Philpot DB, Huber MK, Dong X, Fallon RJ, Bear FM. Internalization of ionotropic glutamate receptors in response to mGluR activation. Nat Neurosci. 2001;4(11):1079-85. Available from: doi:10.1038/nn746. 

13. Revett JT, Baker BG, Jhamandas J, Kar S. Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology. J Psychiatry Neurosci. 2013;38(1):6-23. Available from: doi:10.1503/jpn.110190. 

14. Danysz W, Parsons GC. Alzheimer’s disease, β-amyloid, glutamate, NMDA receptors and memantine – searching for the connections. Br J Pharmacol. 2012;167(2):324-52. Available from: doi:10.1111/j.1476-5381.2012.02057.x.

15. Liu J, Chang L, Song Y, Li H, Wu Y. The Role of NMDA Receptors in Alzheimer’s Disease. Front Neurosci. 2019;13:43. Available from: doi:10.3389/fnins.2019.00043.

16. Wu S, Bodles MA, Porter MM, Griffin TS, Basile SA, Barger WS. Induction of serine racemase expression and D-serine release from microglia by amyloid beta-peptide. J Neuroinflammation. 2004;1(1):2. Available from: doi:10.1186/1742-2094-1-2.

17. Guo W, Wei F, Zou S, Robbins TM, Sugiyo S, Ikenda T, et al. Group I metabotropic glutamate receptor NMDA receptor coupling and signaling cascade mediate spinal dorsal horn NMDA receptor 2B tyrosine phosphorylation associated with inflammatory hyperalgesia. J Neurosci. 2004;24(41):9161-73. Available from: doi:10.1523/JNEUROSCI.3422-04.2004. 

18. Johnson WJ, Kotermanski ES. Mechanism of Action of Memantine. Curr Opin Pharmacol. 2006;6(1):61-7. Available from: doi:10.1016/j.coph.2005.09.007.

19. Lipton AS. Failures and Successes of NMDA Receptor Antagonists: Molecular Basis for the Use of Open-Channel Blockers like Memantine in the Treatment of Acute and Chronic Neurologic Insults. NeuroRX. 2004;1(1):101-10. Available from: doi:10.1602/neurorx.1.1.101. 

20. Pajarillo E, Rizor A, Lee J, Aschner M, Lee E. The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics. Neuropharmacology. 2019;161:107559. Available from: doi:10.1016/j.neuropharm.2019.03.002. 

21. Mutkus L, Aschner LJ, Syversen T, Aschner M. Methylmercury alters the in vitro uptake of glutamate in GLAST- and GLT-1-transfected mutant CHO-K1 cells. Biol Trace Elem Res. 2005;107(3):231-45. Available from: doi:10.1385/BTER:107:3:231. 

22. Rylander D, Recchia A, Mela F, Dekundy A, Danysz W, Cenci A. Pharmacological modulation of glutamate transmission in a rat model of L-DOPA-induced dyskinesia: effects on motor behavior and striatal nuclear signaling. J Pharmacol Exp Ther. 2009;330(1):227-35. Available from: doi:10.1124/jpet.108.150425. 

23. Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci. 2013;14(6):383-400. Available from: doi:10.1038/nrn3504. 

24. Ossowska K, Konieczny J, Wardas J, Pietraszek M, Kuter K, Wolfarth S, et al. An influence of ligands of metabotropic glutamate receptor subtypes on parkinsonian-like symptoms and the striatopallidal pathway in rats. Amino Acid. 2007;32(2):179-188. Available from: doi:https://doi.org/10.1007/s00726-006-0317-y.

25. Phillip MJ, Lam AH, Ackerson CL, Maidment TN. Blockade of mGluR glutamate receptors in the subthalamic nucleus ameliorates motor asymmetry in an animal model of Parkinson’s disease. Eur. J. Neurosci. 2006;23(1):151-60. Available from: doi:https://doi.org/10.1111/j.1460-9568.2005.04550.x.

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