BETA-AMYLOID(1-40) EFFECTS ON BEHAVIOR AND MEMORY

Beta amyloid 1-40 is a primary protein in plaques found in the brains of patients with Alzheimer's disease. There is evidence that unaggregated soluble beta-amyloid may be neurotoxic and may have behavioral effects on some types of memory. In the current study, the 1-40 fragment of beta-amyloid protein ( beta A4), or vehicle, was bilaterally injected into the rostral hippocampus of rats performing under stable food-maintained schedules of reinforcement or under a delayed conditional discrimination procedure. Under the first procedure, rats were trained to stability under a multiple fixed interval 15 s, fixed ratio 30 reinforcement schedule. This reinforcement schedule has proven sensitive to low-dose drug effects. Acute bilateral hippocampal beta A4 (1.0, 2.0 and 3.0 mu l of 10(-3) M) administration did not significantly alter responding, compared to vehicle, under either reinforcement condition. Following the acute single-injection regimen, rats were administered chronic daily beta A4 (1 mu l of 10(-3) M), bilaterally, for 15 days. No significant changes in lever-pressing performance were observed during the chronic injection regimen, but performance declined significantly 30 days after termination of the chronic daily regimen. Histological examination revealed three of six rats showed positive reactions under Thioflavin S staining in and around the area of cannulae termination. The second assessment employed a delayed conditional discrimination procedure to evaluate the effects of intrahippocampal injections of beta A4 on short-term working memory. This conditional discrimination procedure assesses appropriate responding, dependent on a previously presented stimulus, after delays of various lengths have been imposed between the stimulus and the response opportunity. Delay values ranged from 0.01 s to 20 s. Under this procedure, accuracy was unaffected across all delay values following single bilateral intrahippocampal injections of beta A4 (1.0, 2.0 and 3.0 mu l of 10(-3) M). Thus, the soluble unaggregated form of beta A4, injected into the dorsal hippocampus, does not appear to have behavioral effects on performance or short-term working memory in rats, but multiple repeat injections produced performance decrements several weeks later. Repeated injection of beta A4 through indwelling cannulae shows promise for development of an animal model of Alzheimer's disease.