Progressive brain dysfunction following intracerebroventricular infusion of beta(1-42)-amyloid peptide.

The behavioral, neurochemical and histological changes of rats subjected to 3 days treatment with intracerebroventricular infusion of beta-amyloid peptides(Abeta)(1-42) were investigated 20 days and 80 days after the surgery. Abeta(1-42) produced a dose-dependent and a time-dependent impairment in the spontaneous alternation performance in the Y-maze (spatial working memory), place navigation task in a water maze (spatial reference memory) and passive avoidance retention (non-spatial long-term memory) at doses of 10 and 20 microg/rat. The learning impairments were more severe at 80 days than 20 days after infusion of Abeta(1-42). At 25 days after the infusion, a significant decrease in hemicholinium-3 (HC-3) binding was observed only in the hippocampus, although choline acetyltransferase (ChAT) activity was unchanged in the brain regions tested as compared with the vehicle (Abeta(40-1)) treatment. In contrast, the reduction in ChAT activity 85 days after Abeta(1-42) infusion was significant in hippocampus and striatum. HC-3 binding was also significantly decreased in the posterior cortex, hippocampus and striatum. In the histological analysis, brain atrophy was observed inasmuch as ventricular enlargement and neuronal damage in the CA1 area of the hippocampus were seen 85 days after Abeta(1-42) infusion. These results suggest that the rats subjected to intracerebroventricular infusion of Abeta(1-42) suffered from progressive brain dysfunction, and could be useful as an animal model for evaluating the developmental processes at the early and/or middle stage of Alzheimer's-type dementia.