A rabbit model of Alzheimer’s disease based on feeding a cholesterol diet for eight weeks shows sixteen hallmarks of the disease including beta amyloid accumulation and learning and memory changes. Although we have shown that feeding 2% cholesterol and adding copper to the drinking water can retard learning, other studies have shown that feeding dietary cholesterol before learning can improve acquisition and feeding cholesterol after learning can degrade long-term memory. We explore the development of this model, the issues surrounding the role of copper, and the particular contributions of the late D. Larry Sparks. 1. Introduction In 2001, we were looking for nontransgenic animal models of Alzheimer’s disease (AD) in which we could study the effects of potential treatments on AD deficits in learning and memory. A review of the literature revealed very few options other than aged animals that would take many months or even years to reach a point at which they could be studied [1–4]. One exception was a cholesterol-fed rabbit model of AD that Sparks and colleagues showed had several hallmarks of Alzheimer’s pathology, particularly beta amyloid accumulation, that developed in as a little as 8 weeks of being fed a 2% cholesterol diet [5–8]. Surprisingly, given the well-characterized rabbit eyeblink conditioning preparation first published by Gormezano and colleagues in the 1960s [9–13], there were no studies in the literature examining learning and memory in these cholesterol-fed rabbits. We contacted Larry Sparks to ask why no one had published learning and memory studies with this model and the answer was as clear and emphatic as only Larry Sparks could make it: he had tried to convince researchers for years to do the experiments but no one seemed to be interested. One possible reason for this apparent lack of interest in studying learning and memory in a rabbit model of AD was the fact that standard rabbit eyeblink conditioning experiments in which a tone preceded and overlapped with a puff of air to the eye was mediated in large part by the cerebellum [14, 15], and the cerebellum is the last and least affected brain structure in patients with AD [16]. However, this mediation of learning by the cerebellum is only true for the most basic of classical conditioning paradigms known as delay conditioning in which the stimuli overlap [17]. If there is a substantial trace between the two stimuli and the tone and air puff do not overlap, there is good evidence that the hippocampus and prefrontal cortex are engaged and become critical to successful learning and
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