Amidation of β‐Amyloid Peptide Strongly Reduced the Amyloidogenic Activity Without Alteration of the Neurotoxicity

: β‐Amyloid accumulates in cerebral deposits in Alzheimer's disease, so to test the correlation between the neurotoxic and fibrillogenic capacity of β‐amyloid, we synthesized a peptide homologous to fragment 25–35 of β‐amyloid (β25–35) and amidated at the C‐terminus (β25–35‐NH2). As the amidation strongly reduced the amyloidogenic capacity of β25–35, we compared its neurotoxic activity in the amidated (β25–35‐NH2) and nonamidated forms. The viability of primary cultures from fetal rat hippocampus was reduced in a dose‐related manner (10–100 µM) similarly by β25–35 and β25–35‐NH2, whereas a scrambled peptide, amidated or nonamidated, did not alter the neuronal viability. The neurotoxic activity of β25–35‐NH2 is mediated by apoptosis as demonstrated by morphological and biochemical investigations. Electron microscopy examination of culture media with β25–35 or β25–35‐NH2 incubated with neuronal cells for 7 days confirmed the high level of fibrillogenic activity of β25–35 and the almost total absence of fibrils in the solution with β25–35‐NH2. Furthermore, staining with thioflavine S was used to identify amyloid fibrils, and only the cultures exposed to β25–35 exhibited intense staining associated with neuronal membranes. These data indicate that the neurotoxic activity of the β‐amyloid fragment is independent of the aggregated state of the peptide.