Apoptosis-mediated neurotoxicity induced by beta-amyloid and PrP fragments.
The neurotoxic activity of beta-amyloid (beta A) and prion protein (PrP) fragments contributed to the hypothesis concerning a causal role of amyloid deposits in Alzheimer disease (AD) and in prion-related encephalopathies. In this study, we investigated some aspects of the molecular mechanisms associated with neurotoxic activity of synthetic peptides homologous to beta A (beta 25-35) or PrP (PrP106-126) fragments. Chronic (5-7 d) exposure to both peptides induced neuronal death by apoptosis, as suggested by biochemical and morphological analysis. The apoptotic mechanism was confirmed by ultrastructural examination. The intracellular cascade of events activated by peptides was investigated by Northern blot and PCR analysis of expression of early genes (c-fos, c-jun, c-myc) and other proteins (p53, SGP-2 bcl-2, HSP70, Ich-1) potentially involved in apoptosis. With the exception of bcl-2 mRNA decrease and a slight increase of SGP-2 in PrP106-126-treated cells, no consistent alterations of these mRNA expressions were found in neuronal cells exposed to beta 25-35 or PrP106-126. Furthermore, we synthesized amidated homologs of both peptides with low amyloidogenic activity to test directly the relationship between amyloid fibrils and cell death. The neurotoxicity exhibited by PrP106-126-NH2 was similar to that observed with original peptide, whereas the amidation of beta 25-35 partially reduced the neurotoxicity of this peptide.
Forloni
G
G
Istituto di Ricerche, Farmacologiche Mario Negri, Milano, Italy.
Bugiani
O
O
Tagliavini
F
F
Salmona
M
M
D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D005333:Fetus; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D010446:Peptide Fragments / Q000633:toxicity*; D011328:Prions / Q000633:toxicity*; D011519:Proto-Oncogenes / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects
D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments; D011328:Prions; D012333:RNA, Messenger; C074636:amyloid beta-protein (25-35); C082632:prion protein (106-126)