A neurotoxic prion protein fragment induces rat astroglial proliferation and hypertrophy.
Prion-related encephalopathies are characterized by the accumulation of 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 corresponding to residues 106-126 of human PrP is amyloidogenic and causes neuronal 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 homologous to other portions of PrP, a peptide corresponding to residues 25-35 of amyloid-beta protein, and a scrambled sequence of PrP 106-126. No significant changes were observed after 1-day exposure of cultures to any peptide. Conversely, 14-day treatment with PrP 106-126 (50 microM) resulted in a 5-fold increase in glial fibrillary acidic protein (GFAP) expression, as evaluated by Northern and Western blot analyses, and a 1.5-fold increment in cell number. Light and electron microscopy immunohistochemistry showed an enlargement in size and density of astroglial processes, and an increase in GFAP-immunoreactive intermediate filaments. These changes were not observed after 14-day treatment of cultures with the other peptides, including PrP 106-126 scrambled. The increase in GFAP expression of astroglial cultures exposed to PrP 106-126 was quantitatively similar to that found in scrapie-infected hamster brains.(ABSTRACT TRUNCATED AT 250 WORDS)
Forloni
G
G
Alzheimer Neurobiology Unit, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Del Bo
R
R
Angeretti
N
N
Chiesa
R
R
Smiroldo
S
S
Doni
R
R
Ghibaudi
E
E
Salmona
M
M
Porro
M
M
Verga
L
L
D000595:Amino Acid Sequence; D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006984:Hypertrophy; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011328:Prions / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
D005904:Glial Fibrillary Acidic Protein; D009498:Neurotoxins; D010446:Peptide Fragments; D011328:Prions