A rabbit model of Alzheimer's disease: valid at neuropathological, cognitive, and therapeutic levels

Abstract

Supplementing a rabbit's diet with 2% cholesterol alone or with a trace amount of copper created neuropathological changes that resembled those seen in Alzheimer's disease (AD). AD model rabbits were impaired in eyeblink classical conditioning; a form of learning severely impaired in AD. Our aim was to replicate AD rabbit model neuropathology, test eyeblink conditioning in this model, and determine if galantamine (Razadyne) would ameliorate impaired conditioning. In Experiment 1 rabbit chow with 2% cholesterol and drinking water with 0.12 mg/liter copper sulfate were administered for 10 weeks. Control rabbits received normal food and water. Rabbit brains were probed for neuropathology. AD model rabbits had significant neuronal loss in frontal cortex, hippocampus and cerebellum. Changes in neurons in the hippocampus were consistent with neurofibrillary degeneration and cytoplasmic immunoreactivity for amyloid-beta and tau. In Experiment 2 AD model rabbits were injected daily with vehicle or 3.0 mg/kg galantamine and tested on 750 ms trace and delay eyeblink conditioning. Galantamine improved eyeblink conditioning significantly over vehicle. The AD rabbit model has validity from neuropathological to cognitive levels and offers a promising addition to the available animal models of AD. Galantamine ameliorated impaired eyeblink conditioning, extending the validity of the AD rabbit model to treatment modalities.