Amyloid beta peptide alters intracellular vesicle trafficking and cholesterol homeostasis.
Amyloid beta peptide (Abeta) is thought to play a central role in the pathogenesis of Alzheimer disease (AD). How Abeta induces neurodegeneration in AD is not known. A connection between AD and cholesterol metabolism is suggested by the finding that people with the apolipoprotein E4 allele, a locus coding for a cholesterol-transporting lipoprotein, have a modified risk for both late-onset AD and cardiovascular disease. In the present study we show that both Abeta and submicromolar concentrations of free cholesterol alter the trafficking of a population of intracellular vesicles that are involved in the transport of the reduced form of the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT formazan), the formation of which is a widely used cell viability assay. Treatments that change cellular free cholesterol levels also modulate the trafficking of the MTT formazan-containing vesicles, suggesting that the trafficking of these vesicles may be regulated by free cholesterol under physiological conditions. In addition, Abeta decreases cholesterol esterification and changes the distribution of free cholesterol in neurons. These results suggest that the MTT formazan-transporting vesicles may be involved in cellular cholesterol homeostasis and that the alteration of vesicle transport by Abeta may be relevant to the chronic neurodegeneration observed in AD.
Liu
Y
Y
The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Peterson
D A
DA
Schubert
D
D
D016229:Amyloid beta-Peptides / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D002788:Cholesterol Esters / Q000378:metabolism; D004622:Embryo, Mammalian; D005089:Exocytosis; D005562:Formazans / Q000493:pharmacokinetics; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D006706:Homeostasis; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D019301:Oleic Acid / Q000378:metabolism; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000172:deficiency / Q000378:metabolism; D013778:Tetrazolium Salts / Q000493:pharmacokinetics
D016229:Amyloid beta-Peptides; D002788:Cholesterol Esters; D005562:Formazans; D013778:Tetrazolium Salts; C079782:MTT formazan; D019301:Oleic Acid; D002784:Cholesterol; D002785:Sterol O-Acyltransferase