Delayed behavioral effects following intrahippocampal injection of aggregated Aβ (1–42)

Abstract

Beta amyloid protein (Aβ) is the major extracellular component of Alzheimer's disease (AD) plaques. In the current study, Aβ (1–42) was aggregated in vitro using a method which produces Aβ aggregates similar to those found in the AD brain. Twelve male Sprague–Dawley rats were trained in two-lever operant chambers under an alternating lever cyclic-ratio (ALCR) schedule. When performance was stable on the ALCR schedule, six subjects were injected (bilaterally into the CA3 area of the dorsal hippocampus) with 5.0 μl aggregated Aβ in suspension, and the remaining six subjects were injected with 5.0 μl sterile water. Behavioral testing resumed 5 days after surgery and continued for 90 days post-injection. Aggregated Aβ injection did not affect the number of lever switching errors made in a daily session but did affect the number of incorrect lever response perseverations. After approximately 30 days post-injection, aggregated Aβ injection detrimentally affected ability to track the changing parameters of the schedule, and decreased the efficiency by which subjects obtained reinforcers. From approximately day 50 post-injection onward, Aβ-injected subjects demonstrated significantly higher numbers of incorrect lever response perseverations than did sterile water-injected subjects. These effects appeared to be central rather than peripheral, as Aβ injection did not decrease running response rates under the ALCR schedule. The delayed onset of behavioral effects seen in this and other behavioral studies may be a result of a cascade of potentially harmful responses induced through glial activation following aggregated Aβ injection.