title: The effect of exogenous cholesterol and lipid-modulating agents on enterocytic amyloid-beta abundance.
abstract: 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.
authors.affiliation: School of Biomedical Sciences, Curtin University of Technology, Perth, WA, Australia.
authors.forename: Menuka M
authors.initials: MM
authors.lastname: Pallebage-Gamarallage
authors.forename: Susan
authors.initials: S
authors.lastname: Galloway
authors.forename: Russell
authors.initials: R
authors.lastname: Johnsen
authors.forename: Le
authors.initials: L
authors.lastname: Jian
authors.forename: Satvinder
authors.initials: S
authors.lastname: Dhaliwal
authors.forename: John C L
authors.initials: JC
authors.lastname: Mamo
mesh_terms: D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000069059:Atorvastatin; D001384:Azetidines / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage*; D020895:Enterocytes / Q000737:chemistry / Q000378:metabolism*; D000069438:Ezetimibe; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D007408:Intestinal Absorption; D051379:Mice; D008810:Mice, Inbred C57BL; D011758:Pyrroles / Q000494:pharmacology*; D011897:Random Allocation; D014280:Triglycerides / Q000097:blood
chemical_list: D016229:Amyloid beta-Peptides; D000924:Anticholesteremic Agents; D001384:Azetidines; D002791:Cholesterol, Dietary; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D014280:Triglycerides; D002784:Cholesterol; D000069059:Atorvastatin; D000069438:Ezetimibe