Altered Glutamate Reuptake in Relapsing-Remitting and Secondary Progressive Multiple Sclerosis Cortex: Correlation With Microglia Infiltration, Demyelination, and Neuronal and Synaptic Damage
Open accessAbstract
Cortical involvement in multiple sclerosis (MS) is emerging as an important determinant of disease progression. The mechanisms responsible for MS cortical pathology are not fully characterized. The objective of this study was to assess the role of excitotoxicity in MS cortex, evaluating excitatory amino acid transporter (EAAT) expression and its relationship with demyelination, inflammation, gliosis, and neuronal and synaptic pathology. EAATs are essential in maintaining low extracellular glutamate concentrations and preventing excitotoxicity. Ten MS brains (3 relapsing-remitting MS cases and 7 secondary progressive MS cases) were evaluated by immunohistochemistry for myelin basic protein, CD68, HLA-DR, EAAT1, EAAT2, glial fibrillary acidic protein, phosphorylated c-Jun N-terminal kinase (pJNK), synaptophysin, and neurofilaments. Cortical lesions were frequently observed in MS brains in variable numbers and extensions. In cortical lesions, activated microglia infiltration correlated with focal loss of EAAT1, EAAT2, and synaptophysin immunostaining, and with neuronal immunostaining for pJNK, a protein involved in response to excitotoxic injury. No reduction of EAATs or synaptophysin immunostaining was observed in demyelinated cortex in the absence of activated microglia. Alterations of the mechanisms of glutamate reuptake are found in cortical MS lesions in the presence of activated microglia and are associated with signs of neuronal and synaptic damage suggestive of excitotoxicity. Excitotoxicity may be involved in the pathogenesis of demyelination and of neuronal and synaptic damage in MS cortex.
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Loss of synaptic proteins associated with microglial activation has been observed in neuroinflammatory states such as multiple sclerosis and Alzheimer's disease.
“Loss of synaptic proteins associated with microglial activation has been observed in neuroinflammatory states such as multiple sclerosis and Alzheimer's disease (Lue et al., 1996;Vercellino et al., 2007).”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Vercellino et al., 2007
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Peterson, J. W., Bö, L., Mörk, S., Chang, A., & Trapp, B. D. (2001) · Annals of Neurology · doi:10.1002/ana.1123 · Cited by 1,403 · cited 10× · see citing works
“Inflammation in MS cortex was quantified through immunostaining for HLA-DR and CD68 according to methods used in previous reports (1, 7).”
MethodInfluentialDeficient glutamate tranport is associated with neurodegeneration in Alzheimer's disease
Masliah, E., Hansen, L., Alford, M., Deteresa, R., & Mallory, M. (1996) · Annals of Neurology · doi:10.1002/ana.410400512 · Cited by 476 · see citing works
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Research works printed but not linked: 33
- BL L, Vedeler CA, Nyland HI, et al. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol 2003;62:723Y32
- Vercellino M, Plano F, Votta B, et al. Grey matter pathology in multiple sclerosis. J Neuropathol Exp Neurol 2005;64:1101Y7
- Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demyeli- nation and diffuse white matter injury in multiple sclerosis. Brain 2005; 128:2705Y12
- Wegner C, Esiri MM, Chance SA, et al. Neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology 2006;67:960Y67
- BL L, Vedeler CA, Nyland H, et al. Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler 2003;9:323Y31
- Brink BP, Veerhuis R, Breij ECW, et al. The pathology of multiple sclerosis is location-dependent: No significant complement activation is detected in purely cortical lesions. J Neuropathol Exp Neurol 2005;64: 147Y55
- Danbolt NC. Glutamate uptake. Progr Neurobiol 2001;65:1Y105
- Matute C, Domercq M, SanchezYGomez MV. Glutamate-mediated glial injury: Mechanisms and clinical importance. Glia 2006;53:212Y24
- Pitt D, Werner P, Raine CS. Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 2000;6:67Y70
- Smith T, Groom A, Zhu B, Turski L. Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat Med 2000;6:62Y66
- Srinivasan R, Sailasuta N, Hurd R, et al. Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T. Brain 2005;128:1016Y25
- Killestein J, Kalkers NF, Polman CH. Glutamate inhibition in MS: The neuroprotective properties of riluzole. J Neurol Sci 2005;233:113Y15
- Wallstro ¨m E, Diener P, Ljungdahl A, et al. Memantine abrogates neurological deficits, but not CNS inflammation, in Lewis rat experimental autoimmune encephalomyelitis. J Neurol Sci 1996;137: 89Y96
- Rothstein JD, DykesYHoberg M, Pardo CA, et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 1996;16:675Y86
- Domercq M, Etxebarria E, Perez-Samartin A, Matute C. Excitotoxic oligodendrocyte death and axonal damage induced by glutamate transporter inhibition. Glia 2005;52:36Y46
- Merkler D, Bo ¨scke R, Schmelting B, et al. Differential macrophage/ microglia activation in neocortical EAE lesions in the marmoset monkey. Brain Pathol 2006;16:117Y23
- Banner SJ, Fray AE, Ince PG, et al. The expression of the glutamate re-uptake transporter excitatory amino acid transporter 1 (EAAT1) in the normal human CNS and in motor neurone disease: An immunohis- tochemical study. Neuroscience 2002;109:27Y44
- Milton ID, Banner SJ, Ince PG, et al. Expression of the glial glutamate transporter EAAT2 in the human CNS: An immunohistochemical study. Brain Res Mol Brain Res 1997;52:17Y31
- Bonetti B, Stegagno C, Cannella B, et al. Activation of NF-JB and c-jun transcription factors in multiple sclerosis lesions. Implication for oligodendrocyte pathology. Am J Pathol 1999;155:1433Y38
- Trotti D, Rossi D, Gjesdal O, et al. Peroxynitrite inhibits glutamate transporter subtypes. J Biol Chem 1996;271:5976Y79
- Hanisch UK. Microglia as a source and target of cytokines. Glia 2002; 40:140Y55
- Ye ZC, Sontheimer H. Cytokine modulation of glial glutamate uptake: A possible involvement of nitric oxide. Neuroreport 1996;7:2181Y85
- Ohgoh M, Hanada T, Smith T, et al. Altered expression of glutamate Copyright @ 200 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. transporters in experimental autoimmune encephalomyelitis. J Neuro- immunol 2002;125:170Y78
- Werner P, Pitt D, Raine CS. Multiple sclerosis: Altered glutamate homeostasis in lesions correlates with oligodendrocytes and axonal damage. Ann Neurol 2001;50:169Y80
- Vermeiren C, Najimi M, Vanhoutte N, et al. Acute up-regulation of glutamate uptake mediated by mGluR5a in reactive astrocytes. J Neurochem 2005;94:405Y16
- Levi G, Patrizio M. Glutamate production by cultured microglia: Differences between rat and mouse, enhancement by lipopolysaccharide and lack effect of HIV coat protein gp 120 and depolarizing agents. Neurosci Lett 1994;178:184Y88
- Herdegen T, Claret FX, Kallunki T, et al. Lasting N-terminal phosphorylation of c-Jun and activation of c-Jun N-terminal kinases after neuronal injury. J Neurosci 1998;18:5124Y35
- Raivich G, Behrens A. Role of the AP-1 transcription factor c-Jun in developing, adult and injured brain. Prog Neurobiol 2006;78:347Y63
- Yang DD, Kuan CY, Whitmarsh AJ, et al. Absence of excitotoxicity- induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature 1997;389:865Y70
- Minden A, Lin A, McMahon M, et al. Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. Science 1994;266:1719Y23
- Mason MR, Lieberman AR, Anderson PN. Corticospinal neurons up-regulate a range of growth-associated genes following intracortical, but not spinal, axotomy. Eur J Neurosci 2003;18:789Y802
- Ikegaya Y, Kim JA, Baba M, et al. Rapid and reversible changes in dendrite morphology and synaptic efficacy following NMDA receptor activation: Implication for a cellular defense against excitotoxicity. J Cell Sci 2001;114:4083Y93
- Zhu B, Luo L, Moore GR, et al. Dendritic and synaptic pathology in experimental autoimmune encephalomyelitis. Am J Pathol 2003;162: 1639Y50
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Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase
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“Microglial activation has been linked to increased levels of proinflammatory cytokines, oxidative stress (Haider et al., 2011), and altered glutamate reuptake (Vercellino et al., 2007) in MS gray matter, which can all promote excitotoxic injury.”
BackgroundXie, M., Wang, T., Feng, J., Ma, D., Feng, L., & Hao, Y. (2025) · Current Neuropharmacology · doi:10.2174/1570159x23666250225091729 · Cited by 7 · see citing works
- Authors
- Vercellino, M., Merola, A., Piacentino, C., Votta, B., Capello, E., Mancardi, G. L., Mutani, R., Giordana, M. T., & Cavalla, P.
- Affiliations
- University of Turin (IT)
- University of Genoa (IT)
- Corresponding author
- Cavalla, Paola
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-08
- Volume
- 66
- Issue
- 8
- Pages
- 732-739
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- OpenAlex
- W2024309355
- Cited by
- 190
- References
- 2
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 23 · 2023: 9 · 2022: 15 · 2021: 8 · 2020: 12 · 2019: 11 · 2018: 8 · 2017: 5 · 2016: 6 · 2015: 10 · 2014: 10 · 2013: 10 · 2012: 6
- FWCI
- 7.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Zenodo (CERN European Organization for Nuclear Research) (other-oa)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- multiple sclerosis, relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, cortical lesions, glutamate uptake, excitotoxicity, glutamate transporters, GLAST, GLT-1, microglial activation, demyelination, neuronal injury, synaptic damage, synaptophysin, c-Jun N-terminal kinase, neuroinflammation, gliosis
- MeSH terms
- Adult, Aged, Cerebral Cortex, Demyelinating Diseases, Female, Glial Fibrillary Acidic Protein, Humans, Male, Middle Aged, Multiple Sclerosis, Neurons, Postmortem Changes, Synapses, Microglia, Glutamic Acid, Excitatory Amino Acid Transporter 1, Excitatory Amino Acid Transporter 2, Glutamate Plasma Membrane Transport Proteins
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