ALZHEIMER'S AMYLOID BETA FIBRILLOGENESIS: INHIBITION OF APOLIPOPROTEIN E EFFECT BY HIGH DENSITY LIPOPROTEIN LIPID

N.V. Koudinova^1,2, A. Kumar³, T.T. Berezov¹ and A.R. Koudinov^1,2

1. Russian Academy of Medical Sciences, National Mental Health Research Center, Institute of Biomedical Chemistry, Timoshenko 38-27, Moscow 121359, Russian Federation

2. Department of Neurobioliology, Weizmann Institute, Rehovot 76100, Israel

3. Department of Pathology, New York University Medical Center, 560 First Avenue, New York, NY 10016, USA

Amyloid b (Ab) is a major constituent of amyloid deposits in brain tissue of Alzheimer's and Down's syndrome patients and is a normal soluble protein (sAb) in humans. We showed previously that sAb in both normal human plasma and cerebrospinal fluid (CSF) is associated with high density lipoprotein (HDL) and that Ab peptide has extended functions in lipid metabolism (FEBS Letters 1996; 395(2-3), 204-6). We also reported that HDL lipid(particularly phospholipid) contributes to the b-peptide  solubility in biological fluids and inhibits its fibrillogenic b-strand conformation (FASEB J 1997; 11(9), A961; FASEB J 1997; 11(9), A1005). The goal of the present work was to elucidate whether HDL lipid/phospholipid modulates the promotion of Ab fibrillogenesis by apolipoprotein (apo) E. To this end we studied the effect of lipid-free and CSF-HDL lipid particles bound apoE on the Ab1-40 fibrillogenic properties. ApoE was incubated with CSF-HDL lipid particles and apoE-HDL lipid complex was purified then by non-denaturing size exclusion chromatography or density ultracentrifugation. The complex was used for in vitro studies of Ab1-40 fibril formation by SDS/PAGE, immunoblot analysis, ultrastructural electron microscopy, Congo Red staining and thioflavine T assay. The data showed that an increase of the CSF-HDL lipid to apoE molar ratio increased the amount of the Ab peptide remaining soluble in solution. Moreover, both CSF-HDL lipid bound apoE and containing no apoE CSF-HDL lipid particles slowed down the fibrillogenesis of the peptide with the increase of the lipid-to-peptide molar ratio in the similar manner and similar results were obtained with the phospholipid proteoliposomes. These data imply that fibrillogenic potential of Ab increased by apoE may be reversed by the HDL lipid constituent. Change of this interaction in the disease may drive peptide's polymerization into the brain tissue amyloid fibrils.

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