Amyloid β peptide alters intracellular vesicle trafficking and cholesterol homeostasis

Amyloid beta peptide (A beta) is thought to play a central role in the pathogenesis of Alzheimer disease (AD), How A beta 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 A beta 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, A beta 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 A beta may be relevant to the chronic neurodegeneration observed in AD.