Delayed behavioral effects following intrahippocampal injection of aggregated A beta((1-42)

Beta amyloid protein (A beta) is the major extracellular component of Alzhe imer's disease (AD) plaques. In the current study, A beta((1-42)) was aggre gated in vitro using a method which produces A beta aggregates similar to t hose 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 we re injected (bilaterally into the CA3 area of the dorsal hippocampus) with 5.0 mu l aggregated A beta in suspension, and the remaining six subjects we re injected with 5.0 mu l sterile water. Behavioral testing resumed 5 days after surgery and continued for 90 days post-injection. Aggregated A beta i njection did not affect the number of lever switching errors made in a dail y session but did affect the number of incorrect lever response perseverati ons. After approximately 30 days post-injection, aggregated A beta injectio n detrimentally affected ability to track the changing parameters of the sc hedule, and decreased the efficiency by which subjects obtained reinforcers . From approximately day 50 post-injection onward, A beta-injected subjects demonstrated significantly higher numbers of incorrect lever response pers everations than did sterile water-injected subjects. These effects appeared to be central rather than peripheral, as A beta injection did not decrease running response rates under the ALCR schedule. The delayed onset of behav ioral 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 A beta injection. (C) 1999 Elsevier Science B.V. All rights reserved.