ALZHEIMER'S SOLUBLE AMYLOID BETA PROTEIN ASSOCIATION WITH HIGH DENSITY LIPOPROTEIN IN NORMAL HUMAN CEREBRO-SPINAL FLUID: PRIMARY BINDING TO LIPID?

A.R. Koudinov^*,  T.T. Berezov and N.V. Koudinova

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

We have previously described that  in normal human plasma and cerebro-spinal fluid (CSF) the soluble form of Alzheimer's amyloid b protein (sAb) is complexed to high density lipoprotein (HDL). We also reported that in an in vitro system the synthetic homologue of the major HDL associated sAb protein, Ab1-40, is bound to both apolipoprotein (apo) and lipid constituents of plasma HDL. Herein we report further studies of native sAb to HDL association in normal human CSF. Purified CSF-HDLs were subjected to intraparticle cross-linkinking procedure, followed by the reverse phase HPLC fractionation of the lipoprotein. SDS / PAGE and Immunoblot analysis performed then revealed no linkage of CSF-HDL native sAb with the apolipoprotein HDL constituents. In addition, synthetic Ab1-40 to lipid free CSF-HDL apolipoprotein incubation increased the peptide fibrillogenic properties, while protein free CSF-HDL lipid particles bound the peptide and inhibited its fibrillogenesis, as intact CSF-HDL did. This was assesed by density flotation ultracentrifugation, non-denaturing size exclusion HPLC, negative-contrast electron microscopy and thioflavin T assay for b-amyloid fibrils. Our data suggest that under physiologic condition the HDL-lipid constituent plays a primary role in sAb to HDL association and that apolipoprotein modulates an Ab to lipid binding.  Changes of this interaction in the disease may trigger pathologic fibrillogenesis of the peptide.

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