A NEUROTOXIC PRION PROTEIN-FRAGMENT INDUCES RAT ASTROGLIAL PROLIFERATION AND HYPERTROPHY

Prion-related encephalopathies are characterized by the accumulation o f an abnormal prion protein isoform (PrPSc) and the deposition of PrP amyloid in the brain. This process is accompanied by neuronal loss and astrogliosis. We recently showed that a synthetic peptide correspondi ng to residues 106 - 126 of human PrP is amyloidogenic and causes neur onal death by apoptosis in vitro. In the present study we investigated the effects of 1- and 14-day exposures of rat astroglial cultures to micromolar concentrations of this peptide as well as peptides homologo us to other portions of PrP, a peptide corresponding to residues 25 - 35 of amyloid-beta protein, and a scrambled sequence of PrP 106-126. N o significant changes were observed after 1-day exposure of cultures t o any peptide. Conversely, 14-day treatment with PrP 106 - 126 (50 mu M) resulted in a 5-fold increase in glial fibrillary acidic protein (G FAP) expression, as evaluated by Northern and Western blot analyses, a nd a 1.5-fold increment in cell number. Light and electron microscopy immunohistochemistry showed an enlargement in size and density of astr oglial processes, and an increase in GFAP-immunoreactive intermediate filaments. These changes were not observed after 14-day treatment of c ultures with the other peptides, including PrP 106 - 126 scrambled. Th e increase in GFAP expression of astroglial cultures exposed to PrP 10 6 - 126 was quantitatively similar to that found in scrapie-infected h amster brains. These results suggest that the PrP region corresponding to residues 106 - 126 is biologically active, and that cerebral accum ulation of peptides including this sequence might be responsible for b oth the neuronal degeneration and the astrogliosis that occur in prion -related encephalopathies.