Altered glutamate reuptake in relapsing-remitting and secondary progressive multiple sclerosis cortex: correlation with microglia infiltration, demyelination, and neuronal and synaptic damage.
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.
Vercellino
Marco
M
Department of Neuroscience, University of Turin, Turin, Italy.
Merola
Aristide
A
Piacentino
Chiara
C
Votta
Barbara
B
Capello
Elisabetta
E
Mancardi
Giovanni Luigi
GL
Mutani
Roberto
R
Giordana
Maria Teresa
MT
Cavalla
Paola
P
D000328:Adult; D000368:Aged; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003711:Demyelinating Diseases / Q000209:etiology*; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D017628:Microglia / Q000473:pathology*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology* / Q000503:physiopathology; D009474:Neurons / Q000473:pathology*; D011180:Postmortem Changes; D013569:Synapses / Q000473:pathology*
D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D050491:Glutamate Plasma Membrane Transport Proteins; C493397:SLC1A2 protein, human; C493394:SLC1A3 protein, human; D018698:Glutamic Acid