Abstract
BackgroundAmyloid-β (Aβ), a key protein found in amyloid plaques of subjects with Alzheimer's disease is expressed in the absorptive epithelial cells of the small intestine. Ingestion of saturated fat significantly enhances enterocytic Aβ abundance whereas fasting abolishes expression. Apolipoprotein (apo) E has been shown to directly modulate Aβ biogenesis in liver and neuronal cells but it's effect in enterocytes is not known. In addition, apo E modulates villi length, which may indirectly modulate Aβ as a consequence of differences in lipid absorption. This study compared Aβ abundance and villi length in wild-type (WT) and apo E knockout (KO) mice maintained on either a low-fat or high-fat diet. Wild-type C57BL/6J and apo E KO mice were randomised for six-months to a diet containing either 4% (w/w) unsaturated fats, or chow comprising 16% saturated fats and 1% cholesterol. Quantitative immunohistochemistry was used to assess Aβ abundance in small intestinal enterocytes. Apo E KO mice given the low-fat diet had similar enterocytic Aβ abundance compared to WT controls.ResultsThe saturated fat diet substantially increased enterocytic Aβ in WT and in apo E KO mice, however the effect was greater in the latter. Villi height was significantly greater in apo E KO mice than for WT controls when given the low-fat diet. However, WT mice had comparable villi length to apo E KO when fed the saturated fat and cholesterol enriched diet. There was no effect of the high-fat diet on villi length in apo E KO mice.ConclusionThe findings of this study are consistent with the notion that lipid substrate availability modulates enterocytic Aβ. Apo E may influence enterocytic lipid availability by modulating absorptive capacity.
Highlights
Amyloid-β (Aβ), a key protein found in amyloid plaques of subjects with Alzheimer's disease is expressed in the absorptive epithelial cells of the small intestine
High-fat feeding induced hypercholesterolemia in apo E KO mice Apo E KO mice given low-fat chow had significantly elevated plasma cholesterol compared to WT mice on the low-fat diet, plasma triglycerides were not significantly affected because of the gene deletion
Immunolocalisation of Aβ in the small intestine of apolipoprotein E KO mice: synergistic effects of high fat feeding For all groups of mice, Aβ immunostaining was demonstrated within the perinuclear region of absorptive columnar epithelial cells of the small intestine mucosa
Summary
Amyloid-β (Aβ), a key protein found in amyloid plaques of subjects with Alzheimer's disease is expressed in the absorptive epithelial cells of the small intestine. Apolipoprotein (apo) E has been shown to directly modulate Aβ biogenesis in liver and neuronal cells but it's effect in enterocytes is not known. This study compared Aβ abundance and villi length in wild-type (WT) and apo E knockout (KO) mice maintained on either a low-fat or high-fat diet. Apo E KO mice given the low-fat diet had similar enterocytic Aβ abundance compared to WT controls. Apolipoprotein E may modulate cerebral Aβ homeostasis by regulating cerebral Aβ efflux via the low-density-lipoprotein-receptorrelated protein (LRP), relative to the influx of Aβ via transporters such as the receptor for advanced-glycation-endproducts (RAGE) [9]. The apo E protein is the primary receptor ligand for dietary-derived lipoproteins synthesized by the small intestine (chylomicrons) and triglyceride-rich lipoproteins (very-low-density lipoproteins (VLDL)), synthesized from liver [12]. Animals given saturated-fat diets show significant immuno-detectable cerebral Aβ burden [18,19,20], the mechanisms by which this occurs are presently unclear
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