The cholesterol-fed rabbit is a model of atherosclerosis and has been proposed as an animal model of Alzheimer's disease. Feeding rabbits cholesterol has been shown to increase the number of beta amyloid immunoreactive neurons in the cortex. Addition of copper to the drinking water of cholesterol-fed rabbits can increase this number still further and may lead to plaque-like structures. Classical conditioning of the nictitating membrane response in cholesterol-fed rabbits is retarded in the presence of these plaque-like structures but may be facilitated in their absence. In a factorial design, rabbits fed 2% cholesterol or a normal diet (0% cholesterol) for 8 weeks with or without copper added to the drinking water were given trace classical conditioning using a tone and periorbital electrodermal stimulation to study the effects of cholesterol and copper on classical conditioning of heart rate and the nictitating membrane response. Cholesterol-fed rabbits showed significant facilitation of heart rate conditioning and conditioning-specific modification of heart rate relative to normal diet controls. Consistent with previous research, cholesterol had minimal effects on classical conditioning of the nictitating membrane response when periorbital electrodermal stimulation was used as the unconditioned stimulus. Immunohistochemical analysis showed a significant increase in the number of beta amyloid positive neurons in the cortex, hippocampus and amygdala of the cholesterol-fed rabbits. Supplementation of drinking water with copper increased the number of beta amyloid positive neurons in the cortex of cholesterol-fed rabbits but did not produce plaque-like structures or have a significant effect on heart rate conditioning. The data provide additional support for our finding that, in the absence of plaques, dietary cholesterol may facilitate learning and memory. Cholesterol enhances rabbit heart rate conditioningThe cholesterol-fed rabbit has been used as an animal model of atherosclerosis since 1913 when Anitchkow first demonstrated that a cholesterol diet induced vascular lesions (Bocan, 1998;Fan & Watanabe, 2000;Finking & Hanke, 1997;Moghadasian, 2002). More recently, the cholesterol-fed rabbit has been proposed as an animal model of Alzheimer's disease (Ghribi, Larsen, Schrag, & Herman, 2006;Sjogren, Mielke, Gustafson, Zandi, & Skoog, 2006 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Sparks, 1997;Sparks, Martin, Gross, & Hunsaker III, 2000;Zatta, Zambenedetti, Stella, & Licastro, 2002). Based on the observation that patients with heart disease had beta amyloid st...

One of the hallmarks of Alzheimer’s Disease is a significant increase in ventricular volume. To date we and others have shown that a cholesterol-fed rabbit model of Alzheimer’s Disease displays as many as fourteen different pathological markers of Alzheimer’s Disease including amyloid β accumulation, thioflavin-S staining, blood brain barrier breach, microglia activation, cerebrovasculature changes and alterations in learning and memory. Using structural magnetic resonance imaging at 3T we now report that cholesterol-fed rabbits also show a significant increase in ventricular volume following 10 weeks on a diet of 2% cholesterol. The increase in volume is attributable in large part to increases in the size of the third ventricle. These changes are accompanied by significant increases in the number of amyloid β immuno-positive cells in the cortex and hippocampus. Increases in the number of beta amyloid neurons in the cortex also occurred with the addition of 0.24 ppm copper to the drinking water. Together with a list of other pathological markers, the current results add further validity to the value of the cholesterol-fed rabbit as a non-transgenic animal model of Alzheimer’s disease.