PRION PROTEIN-FRAGMENT-106-126 DIFFERENTIALLY INDUCES HEME OXYGENASE-1 MESSENGER-RNA IN CULTURED NEURONS AND ASTROGLIAL CELLS

Heme oxygenase (HO), which catalyzes the degradation of heme, has two isozymes (HO-1 and HO-2), In brain the noninducible HO-2 isoform is pr edominant, whereas the inducible HO-1 is a marker of oxidative stress, Because brain oxidative stress might be present in prion-related ence phalopathies (PREs), as in other neurodegenerative diseases, we invest igated whether HO-1 mRNA was induced in neuronal and astroglial cell c ultures by a peptide corresponding to residue 106-126 of human prion p rotein (PrP). This peptide is amyloidogenic, and when added in vitro t o cultured cells it reproduces the neuronal death and astroglial proli feration and hypertrophy occurring in PREs, HO-1 mRNA did not accumula te in rat cultured neurons from hippocampus or cortex exposed to PrP 1 06-126 (50 mu M for 5 days). PrP 106-126 induced HO-1 mRNA accumulatio n in rat astroglial cultures depending on the exposure time and concen tration, being maximal (33-fold) after 7 days of exposure at 50 mu M. The nonamyloidogenic amidated or amidated-acetylated PrP 106-126 was i neffective, as was a scrambled peptide used as control. N-Acetylcystei ne reduced (50%) the accumulation of HO-1 mRNA in astroglial cells aft er PrP 106-126 (25 mu M) given for 5 days. Thus, oxidative stress is a pparently a feature of the toxicity of PrP 106-126, and it might also occur in PREs; induction of HO-1 could contribute to the greater resis tance of astrocytes compared with neurons to PrP 106-126 toxicity.