MULTIPLE INHIBITORY EFFECTS OF ALZHEIMER'S PEPTIDE Ab1-40 ON LIPID BIOSYNTHESIS IN HepG2 CELLS
A.R. Koudinov, N.V. Koudinova and T.T. Berezov
Russian Academy of Medical Sciences, National Mental Health Research Center, Institute of Biomedical Chemistry, Timoshenko 38-27, Moscow 121359, Russian Federation
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 previously that Ab in both normal plasma and cerebrospinal fluid is associated with high density lipoproteins. This imply that sAb may have some function(s) in lipid metabolism, as many other protein constituents of lipoproteins, different apolipoproteins, do. Our recent observation of inhibition of normal plasma cholesterol esterification by synthetic Ab peptides (Biochem Mol Biol Internat 1996, Vol. 38, 4, 747-752) support this assessment. Herein we report the inhibitory 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), the major constituents of biological membranes. Synthesis of triacylglycerols was also reduced but to a lower extent. Our data suggest that Ab has extended functions in lipid metabolism. The observed effect may be of special importance in pathological condition, and contribute to the neurodegeneration, in Alzheimer's disease and related disorders.
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