Immunotherapy in a hypercholesterolemic rabbit model of Alzheimer's disease

The cholesterol-fed rabbit model of AD with its close parallels to human genetics and physiology, along with its validity as a model of human AD, provides an interesting vehicle for testing immunotherapies for AD. Our initial work confirmed that cholesterol-fed rabbits treated with Abeta immunotherapy generate high anti-Abeta antibody titers and reduced levels of Abeta in hippocampus. Now in Expt 1 (E-1) we addressed immunotherapy, brain Abeta and learning and in Expt 2 (E-2) we focused on the potential of an immunotherapeutic regimen to prevent accumulation of brain Abeta and learning impairment. Rabbits were fed a cholesterol/trace copper diet for 10 weeks. In E-1, 4 groups of rabbits were immunized 5X with Abeta1-42 peptide coupled to KLH (Table 1). In E-2, rabbits were inoculated 4X over a 10-week period before the cholesterol/trace copper diet (Table 2). Plasma was analyzed by ELISA for anti-Abeta antibodies. Brains were immunostained for Abeta (Clone 6E10, Covance SIGNET line) and analyzed for intercellular Abeta and extracellular Abeta plaques. Results of ELISAs indicate that cholesterol-fed rabbits treated with Abeta immunotherapy generated anti-Abeta responses. In E-1, concentration of plasma anti-Abeta antibodies in inoculated male rabbits was significantly greater than in non-inoculated rabbits. In older female rabbits anti-Abeta antibodies increased with and without inoculation. The inoculations did not ameliorate impaired eyeblink conditioning. The amount of brain Abeta in inoculated female rabbits is about 86% of the brain Abeta in older female rabbits that were not inoculated. The amount of brain Abeta in inoculated young male rabbits actually exceeded the amount in non-inoculated rabbits. A longer interval between inoculations appears to be a key factor in optimizing treatment, at least in the young male AD model rabbits. Abeta inoculation of young AD model rabbits resulted in an increase in plasma anti-Abeta antibodies in E-1 and E-2, whereas in older female rabbits anti-Abeta antibodies increased with and without inoculation. Acquisition of conditioned eyeblink responses was not different between inoculated and non-inoculated young and older rabbits. These results with a behavioral assessment of learning are consistent with recent studies in Abeta-inoculated human AD patients and canines.