A rabbit model of Alzheimer’s disease based on feeding a cholesterol diet for eight weeks shows sixteen hallmarks of the disease, including learning and memory changes. Although we have shown 2% cholesterol and copper in water can retard learning, other studies show feeding dietary cholesterol before learning can improve acquisition whereas feeding cholesterol after learning can degrade long-term memory. We explored this issue by manipulating cholesterol concentration and duration following classical trace conditioning of the rabbit’s nictitating membrane response and assessed conditioned responding after eight weeks on cholesterol. First, rabbits given trace classical conditioning followed by 0.5%, 1%, or 2% cholesterol for eight weeks showed body weight and serum cholesterol levels that were a function of dietary cholesterol. Although all concentrations of cholesterol showed some sign of retarding long-term memory, the level of memory retardation was correlated with serum cholesterol levels. Second, rabbits given trace conditioning followed by different durations of a 2% cholesterol diet combined with different durations of a 0% control diet for 8 weeks showed duration and timing of a 2% cholesterol diet were important in affecting recall. The data support the idea that dietary cholesterol may retard long-term memory. 1. Introduction In rabbits fed 2% cholesterol for as little as eight weeks, there are as many as sixteen different indices of pathology that are similar to those seen in Alzheimer’s Disease (AD) including intracellular and extracellular Aβ, breaches of the blood brain barrier, activation of microglia, apoptosis, increased levels of Apolipoprotein E, phosphorylated tau protein, changes in the cerebrovasculature, and increases in ventricular volume [1–12]. Coinciding with these changes in brain pathology, there have been reports of detrimental effects on learning [6, 13–16]. Nevertheless, research with this and other animal models suggests that modifying dietary cholesterol can in many cases improve learning and memory. For instance, increasing cholesterol in young DBA/2 mutant mice improves performance on the Morris water maze—a spatial learning task that is normally impaired in this mutant [17, 18]. Feeding cholesterol to young, normal rats also improves performance on the Morris water maze [19]. Feeding cholesterol to rats that are either deficient in cholesterol or have cholesterol synthesis blocked reverses problems with learning and memory [20–23]. We have also shown that feeding rabbits cholesterol can facilitate classical
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