Neuropathology of synthetic beta-amyloid peptide analogs in vivo

Considerable evidence exists demonstrating that beta-amyloid protein and its fragments 1-40 and 25-35 (beta (25-35)) are neurotoxic to cells in the rat hippocampus both in culture and in vivo. This neurotoxicity has been correlated to the aggregational state of the peptides. Previously we have shown that beta (25-35) produces a cavitational lesion in rat hippocampus and also reduces the enzyme or transmitter expressions in two subcortical structures whose axons project to the hippocampus: the locus coeruleus (LC) and the medial septum. In the present study, we further investigated the amino acid sequence that might be responsible for these effects. A series of synthetic peptide analogs of beta (25-35) with glycine substituted for serine, asparagine, lysine and methionine at positions 26, 27, 28 and 35, respectively, were injected at a 3 nmol dosage into the rat hippocampus once a week for 2 weeks. The damage to the hippocampus and immunohistochemistry of the LC and medial septum were examined 1 week following the second treatment. All of the synthetic peptides with glycine substitution produced damage to the hippocampal tissue. This damage was similar to that seen with beta (25-35). However, the reduction of enzyme expressions in the LC and medial septum was less from these substituted peptides than from that of beta (25-35). While beta (25-35) application resulted in a similar reduction of tyrosine hydroxylase (TH) and glutamate (Glu) immunoreactivities in the LC, only TH was significantly reduced in the substituted peptide groups. The least reduction of TH and Glu immunoreactivities in the LC was observed in rats treated with peptides in which glycine replaced either lysine or methionine. In the basal forebrain medial septum, the application of beta (25-35) resulted in a marked decrease in choline acetyltransferase (ChAT) immunoreactivity. This reduction was found to be less by each of the synthetic peptides. These results suggest that the biological activity of beta (25-35) is sensitive to changes in the primary structure of the peptide. Among the 4 amino acid residues examined, lysine and methionine at positions 28 and 35 appear to play more important roles in determining the action of beta (25-35).