Long-term changes in the aggregation state and toxic effects of beta-amyloid injected into the rat brain.

The long-term effects of beta-amyloid peptide 1-40 injection into the rat forebrain were studied. Ten micrograms of pre-aggregated peptide were injected into the right nucleus basalis of male Wistar rats which were then killed four or six months later. Congo Red staining of histological sections showed that the peptide deposit was aggregated in a fibrillary form four months post-surgery, whereas at six months almost no trace of birefringency was detected at the deposit site, indicating a loss of fibril organization. This result was confirmed by electron microscopic analysis of the peptide deposits. The presence of the peptide at the injection site six months post-surgery was demonstrated by both Haematoxylin staining and beta-amyloid immunoreactivity. The number of choline acetyltransferase-immunoreactive neurons was reduced by 66% in the injected nucleus basalis four months after injection. A decrease in cortical acetylcholine release was also found at this time. Concomitantly with the loss of fibril conformation, a complete recovery of choline acetyltransferase immunoreactivity in the nucleus basalis and of acetylcholine release in the cortex was observed at six months. These data provide in vivo evidence that beta-amyloid neurotoxicity is related to the fibrillary conformation of the peptide aggregates, thus confirming previous in vitro studies.