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Dietary cholesterol may influence Alzheimer's disease risk, because it regulates the synthesis of amyloid-beta. It was recently demonstrated in enterocytes of wild-type mice that intracellular amyloid-beta expression is enhanced in response to a high-fat diet made up of SFA and cholesterol. Intestinally derived amyloid-beta may be associated with postprandial lipoproteins in response to dietary fats and could be a key regulator in chylomicron metabolism. The present study was designed to investigate the role of cholesterol in modulating amyloid-beta abundance in enterocytes. Wild-type mice were fed a low-fat diet supplemented with 2 % (w/w) cholesterol. The effects of cholesterol absorption inhibition and cholesterol biosynthesis inhibition utilising ezetimibe and atorvastatin, respectively, were also studied. Quantitative immunohistochemistry was utilised to determine enterocytic amyloid-beta homeostasis. We found that enterocytic amyloid-beta concentration was significantly attenuated in mice fed the 2 % (w/w) cholesterol diet. However, blocking cholesterol absorption reversed the cholesterol-feeding effect. Consistent with a suppressive effect of cholesterol on enterocytic amyloid-beta abundance, atorvastatin, an inhibitor of cholesterol biosynthesis, enhanced amyloid-beta. However, providing exogenous cholesterol abolished the atorvastatin-induced effect. In contrast to the suppression of enterocytic amyloid-beta by dietary cholesterol, mice fed a diet enriched in SFA had markedly greater abundance. Collectively, the findings suggest that exogenous and endogenous cholesterol reduce amyloid-beta concentration in enterocytes by suppressing production, or enhancing secretion associated with postprandial lipoproteins. Intestinally derived amyloid-beta will contribute to the pool of plasma protein and may influence cerebral amyloid homeostasis by altering the bi-directional transfer across the blood-brain barrier.

Original publication

DOI

10.1017/S0007114508012269

Type

Journal article

Journal

Br J Nutr

Publication Date

02/2009

Volume

101

Pages

340 - 347

Keywords

Amyloid beta-Peptides, Animals, Anticholesteremic Agents, Atorvastatin Calcium, Azetidines, Body Weight, Cholesterol, Cholesterol, Dietary, Enterocytes, Ezetimibe, Female, Heptanoic Acids, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Immunohistochemistry, Intestinal Absorption, Mice, Mice, Inbred C57BL, Pyrroles, Random Allocation, Triglycerides