Abstract
BackgroundRabbits maintained on high-cholesterol diets are known to show increased immunoreactivity for amyloid beta protein in cortex and hippocampus, an effect that is amplified by presence of copper in the drinking water. Hypercholesterolemic rabbits also develop sporadic neuroinflammatory changes. The purpose of this study was to survey microglial activation in rabbits fed cholesterol in the presence or absence of copper or other metal ions, such as zinc and aluminum.MethodsVibratome sections of the rabbit hippocampus and overlying cerebral cortex were examined for microglial activation using histochemistry with isolectin B4 from Griffonia simplicifolia. Animals were scored as showing either focal or diffuse microglial activation with or without presence of rod cells.ResultsApproximately one quarter of all rabbits fed high-cholesterol diets showed evidence of microglial activation, which was always present in the hippocampus and not in the cortex. Microglial activation was not correlated spatially with increased amyloid immunoreactivity or with neurodegenerative changes and was most pronounced in hypercholesterolemic animals whose drinking water had been supplemented with either copper or zinc. Controls maintained on normal chow were largely devoid of neuroinflammatory changes, but revealed minimal microglial activation in one case.ConclusionBecause the increase in intraneuronal amyloid immunoreactivity that results from administration of cholesterol occurs in both cerebral cortex and hippocampus, we deduce that the microglial activation reported here, which is limited to the hippocampus, occurs independent of amyloid accumulation. Furthermore, since neuroinflammation occurred in the absence of detectable neurodegenerative changes, and was also not accompanied by increased astrogliosis, we conclude that microglial activation occurs because of metabolic or biochemical derangements that are influenced by dietary factors.
Highlights
Rabbits maintained on high-cholesterol diets are known to show increased immunoreactivity for amyloid beta protein in cortex and hippocampus, an effect that is amplified by presence of copper in the drinking water
Controls maintained on regular chow and dH2O with or without copper ion added showed no evidence of microglial activation in 7 out of 8 animals (Table 1, Figs. 1A,C,D)
Microglial activation was evident by the presence of multiple foci of intensified lectin staining (e.g. Figs. 2A,B) and/or by a more diffuse presence of activated microglial cells throughout the dentate gyrus and the stratum lacunosum moleculare (Fig. 2C)
Summary
Rabbits maintained on high-cholesterol diets are known to show increased immunoreactivity for amyloid beta protein in cortex and hippocampus, an effect that is amplified by presence of copper in the drinking water. Perhaps most relevant is the fact that addition of cholesterol to the diet consistently results in increased immunoreactivity for amyloid beta protein within neurons of the cerebral and hippocampal cortices of these animals [3,4] Inflammatory changes, such as microglial activation and leukocyte extravasation, have been reported in cholesterol-fed rabbits, but unlike the enhanced accumulation of amyloid neuroinflammatory changes are not found uniformly in all hypercholesterolemic animals [5]. We have assumed that the inciting stimulus for neuroinflammation is provided by the increase in amyloid beta protein that results from high serum cholesterol levels This assumption seemed reasonable in light of large numbers of studies reporting proinflammatory effects of amyloid beta peptides over many years [6,7,8,9,10,11,12,13,14]
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