Cholesterol Increases Ventricular Volume in a Rabbit Model of Alzheimer's Disease

Abstract

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.

A High-Cholesterol Diet Increases 27-Hydroxycholesterol and Modifies Estrogen Receptor Expression and Neurodegeneration in Rabbit Hippocampus

“…The cholesterol-fed rabbit model of AD shows a multitude of pathological findings similar to those seen in AD patients including Aβ deposits, neurofibrillary tangles, apoptosis, microglia activation, and increased ventricular volume [12, 13, 39, 40] as well as cognitive deficits [17–21]. Here we also demonstrated that a high-cholesterol diet is associated with significant levels of neurodegeneration in the hippocampus.…”

Intrinsic connectivity of neural networks in the awake rabbit

“…Many of the same networks found in humans, non-human primates, and rodents are also found in the rabbit. Our findings provide the first examination of the rabbit as a potential animal model for translational research studying neural networks and provide the baseline data for changes that may occur during different behavioral states or disease states such as Alzheimer's disease (Deci et al, 2012; Liu et al, 2012; Perez-Garmendia et al, 2014; Schreurs et al, 2013). …”

Cholesterol and Copper Affect Learning and Memory in the Rabbit

“…Importantly, although we continued to see higher levels of beta amyloid immunoreactivity with copper added to the drinking water of cholesterol-fed rabbits compared to those on distilled water, there was no evidence of extracellular beta amyloid plaques. This was even true when we doubled the copper concentration in the drinking water to 0.24 ppm although, in that case, the cortical levels of beta amyloid immunoreactivity were significantly higher in chow-fed rabbits given 0.24 ppm copper compared to those given distilled water suggesting that copper by itself was having an effect on beta amyloid accumulation [61]. …”

“…At the conclusion of many of our behavioral experiments, we began structural MRI imaging of the rabbits' brains to explore the effects of cholesterol and copper on rabbit ventricular volume [61, 67] and cerebrovascular diameter [67]—indices that have been noted to change in patients with AD [68–71]. The four panels of Figure 4 show structural MRI scans of rabbits that received normal chow and distilled water (a), normal chow and 0.12 ppm copper added to the distilled water (b), 2% cholesterol and distilled water (c), and 2% cholesterol and copper (d), with insets that show the area of the third ventricle.…”

“…The data in Figure 4 illustrate clearly that a cholesterol diet significantly increased the area of the third ventricle and consequently, when the entire rabbit brain was analyzed, the volume of the third ventricle was found to be higher for the cholesterol-fed rabbits than the normal chow-fed controls [72]. This was true regardless of whether the rabbits were given copper in the drinking water or whether the concentration of that copper was 0.12 ppm [72] or 0.24 ppm [61]. In all of these experiments, the levels of beta amyloid immunoreactivity to the 10D5 antibody was always higher in cholesterol-fed rabbits than normal chow controls, and the addition of copper tended to increase the intensity of that immunoreactivity even further although this copper-induced increase was not always significantly higher [48–50, 61].…”