EFFECT OF ALZHEIMER'S Ab PEPTIDE ON PLASMA CHOLESTEROL ESTERIFICATION AND LIPID BIOSYNTHESIS IN HEPG2 CELLS
A.R. Koudinov; T.T. Berezov; N.V. Koudinova
Russian Academy of Medical Sciences, National Mental Health Research Center, Institute of Biomedical Chemistry, Timoshenko 38-27, Moscow 121359, Russia
Alzheimer's amyloid b protein (Ab) is a major constituent of amyloid fibrils of brain tissue of Alzheimer's and Down's syndrome patients and of normal aged individuals. Since 1992, when amyloid b was detected in a soluble form (sAb) in plasma, cerebrospinal fluid and cell culture's supernatants, it became clear that Ab, considered long a pathological protein only, is a normal and constitutive product of its amyloid precursor protein. We showed recently that Ab in both normal plasma and cerebrospinal fluid is associated with high density lipoproteins. These and other facts prompted us to ascertain whether there is a function of Ab peptide related to cholesterol metabolism and whether it affects cellular lipid synthesis. For this purpose we tested the effect of synthetic Ab1-40 and Ab1-28 on plasma cholesterol esterification rate. Both peptides at a concentration of 1 ng/ml inhibited plasma cholesterol esterifi-cation rate to 40-50 % of control value. Statistical analysis showed no differences in the effect of Ab1-40 and Ab1-28 on the inhibition, suggesting the importance of Ab sequence 1-28 for this effect. We also tested the effect of synthetic peptide Ab1-40, homologous to the major circulatory and high density lipoprotein associated species of Alzheimer's sAb, on lipid biosynthesis in human hepatic HepG2 cells. This culture synthesizes various lipids from [14C]-acetate as a precursor. Treatment of cells with different concentrations of Ab1-40 decreased the syntheses of various radiolabeled lipid species. The decrease reached saturation at the concentration of Ab equal to 10 ng per ml of media. The lipids whose synthesis was decreased most were free and esterified cholesterol and phospholipids (25-40 % maximum inhibition). Synthesis of triacylglycerols was also reduced but to a lower extent. Our data suggest that Ab has extended functions in lipid metabolism. In addition, the observed effects may be of special importance in pathological condition, and contribute to the neurodegeneration, in Alzheimer's disease and related disorders.
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