title: Expression of excitatory amino acid transporter-1 (EAAT-1) in brain macrophages and microglia of patients with prion diseases.
abstract: The mechanisms of neuronal apoptosis in prion diseases are unclear. Experimental studies suggest that it may result from 2 associated mechanisms: glutamate-mediated excitotoxicity and oxidative stress. Recent studies showed that activated macrophages/microglia (AMM) express excitatory amino acid transporters (EAATs) in HIV infection, suggesting that they may play a neuroprotective role by clearing extra-cellular glutamate and producing anti-oxidant glutathione. In order to test this hypothesis in prion diseases, samples from cerebral cortex, striatum, thalamus, and cerebellum from 14 patients with Creutzfeldt-Jakob disease (8 sporadic, 2 familial, 2 iatrogenic, and 2 variant), and 4 with fatal familial insomnia (3 homozygous Met/Met at codon 129 of the PRNP gene, 1 heterozygous Met/Val), and 3 controls were immunostained for EAAT-1, GFAP, HLA-DR, CD68, IL-1, caspase 3, and PrP. In prion diseases, EAAT-1 immunopositivity was found in affected areas. Only AMM, interstitial, perivascular, perineuronal (sometimes around apoptotic neurons), or close to reactive astrocytes, expressed EAAT-1. Astrocyte EAAT-1 expression was scarcely detectable in controls and was not detected in prion disease cases. The proportion of AMM expressing EAAT-1 did not correlate with the severity of neuronal apoptosis, spongiosis, astrocytosis, microgliosis, or PrP deposition, but only with disease duration. Occasional EAAT-1 expressing AMM were found in patients with short survival, whereas diffuse EAAT-1 expression by AMM was observed in cases with long survival (24 to 33 months) that most often were heterozygous for Met/Val at codon 129 of the PRNP gene. Our findings suggest that AMM may develop a partial neuroprotective function in long-lasting prion diseases, although it does not seem to efficiently prevent neurological and neuropathological deterioration. Whether this neuroprotective function of microglia is the cause or the effect of longer survival needs to be clarified.
authors.affiliation: INSERM EMI0011 and Département de Pathologie, Hôpital Henri Mondor, Assistance Publique-Hôpital de Paris, Créteil, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Chrétien
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Le Pavec
authors.forename: Anne-Valérie
authors.initials: AV
authors.lastname: Vallat-Decouvelaere
authors.forename: Marie-Bernadette
authors.initials: MB
authors.lastname: Delisle
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Uro-Coste
authors.forename: James W
authors.initials: JW
authors.lastname: Ironside
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
authors.forename: Piero
authors.initials: P
authors.lastname: Parchi
authors.forename: Christophe
authors.initials: C
authors.lastname: Créminon
authors.forename: Dominique
authors.initials: D
authors.lastname: Dormont
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Mikol
authors.forename: Francoise
authors.initials: F
authors.lastname: Gray
authors.forename: Gabriel
authors.initials: G
authors.lastname: Gras
mesh_terms: D000328:Adult; D000368:Aged; D000682:Amyloid / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D003062:Codon; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism*; D005260:Female; D006579:Heterozygote; D006801:Humans; D034062:Insomnia, Fatal Familial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008715:Methionine; D017628:Microglia / Q000378:metabolism*; D008875:Middle Aged; D000072002:Prion Proteins; D011328:Prions; D011498:Protein Precursors / Q000235:genetics; D012720:Severity of Illness Index; D013997:Time Factors; D014633:Valine
chemical_list: D000682:Amyloid; D003062:Codon; D027341:Excitatory Amino Acid Transporter 1; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D011498:Protein Precursors; D008715:Methionine; D014633:Valine