APOPTOSIS-MEDIATED NEUROTOXICITY INDUCED BY BETA-AMYLOID AND PRP FRAGMENTS

The neurotoxic activity of beta-amyloid (beta A) and prion protein (Pr P) fragments contributed to the hypothesis concerning a causal role of amyloid deposits in Alzheimer disease (AD) and in prion-related encep halopathies. In this study, we investigated some aspects of the molecu lar mechanisms associated with neurotoxic activity of synthetic peptid es homologous to beta A (beta 25-35) or PrP (PrP106-126) fragments. Ch ronic (5-7 d) exposure to both peptides induced neuronal death by apop tosis, as suggested by biochemical and morphological analysis. The apo ptotic mechanism was confirmed by ultrastructural examination. The int racellular 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-l) poten tially involved in apoptosis. With the exception of bcl-2 mRNA decreas e and a slight increase of SGP-2 in PrP106-126-treated cells, no consi stent alterations of these mRNA expressions were found in neuronal cel ls exposed to beta 25-35 or PrP106-126. Furthermore, we synthesized am idated homologs of both peptides with low amyloidogenic activity to te st directly the relationship between amyloid fibrils and cell death. T he neurotoxicity exhibited by PrP106-126-NH2 was similar to that obser ved with original peptide, whereas the amidation of beta 25-35 partial ly reduced the neurotoxicity of this peptide.