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Amino‐Terminally Truncated Prion Protein PrP90‐231 Induces Microglial Activation in Vitro
Author(s) -
THELLUNG STEFANO,
CORSARO ALESSANDRO,
VILLA VALENTINA,
VENEZIA VALENTINA,
NIZZARI MARIO,
BISAGLIA MICHELA,
RUSSO CLAUDIO,
SCHETTINI GENNARO,
ACETO ANTONIO,
FLORIO TULLIO
Publication year - 2007
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1397.092
Subject(s) - microglia , proinflammatory cytokine , microbiology and biotechnology , in vitro , secretion , extracellular , kinase , recombinant dna , biology , programmed cell death , nitric oxide synthase , nitric oxide , chemistry , biochemistry , inflammation , immunology , enzyme , apoptosis , endocrinology , gene
: The conversion of the prion protein (PrP) into a protease‐resistant isoform (PrP Res ) is considered the pathogenic event responsible for prion encephalopathies. Microglia activation accompanies PrP Res deposition representing an early event in the progression of these diseases. It is now believed that microglial cells play a worsening, if not causative, role in prion‐induced neuronal death, through the release of proinflammatory and neurotoxic molecules. Indeed, in vitro observations have demonstrated that PrP Res and the synthetic prion fragment PrP106‐126 induce neuronal death by activating microglial to migrate in the lesion area and secrete cytokines. Recently, we and others have demonstrated that the recombinant peptide, corresponding to the protease‐resistant portion of PrP encompassing the amino acids 90‐231 (PrP90‐231), when β‐structured, is toxic for neuronal cells, in vitro . Here we report that PrP90‐231 induces activation of N9 microglial cells, characterized by cell proliferation arrest and increased secretion of different cytokines (RANTES, GCSF, and IL‐12). Moreover, the treatment of N9 cells with PrP90‐231 elicited inducible nitric oxide synthase (i‐NOS) expression, nitric oxide release, and a delayed (15 min to 1 h of treatment) extracellular signal‐regulated kinases 1/2 (ERK1/2) phosphorylation/activation. Although ERK1/2 is known to regulate proliferative and differentiative events, we show that its blockade, using the specific MEK inhibitor PD98059, did not prevent PrP90‐231‐induced inhibition of N9 cell proliferation. To our knowledge, this is the first evidence that a recombinant PrP Res ‐like peptide elicits microglial activation in vitro, thus representing a potentially important tool to develop possible therapeutic strategies to target prion‐induced brain inflammation.