Cerebrovascular and parenchymal amyloid deposits found in brains of Alzheimer's disease, Down's syndrome and normal aging are mainly composed of aggregated amyloid beta protein (A beta), a unique peptide 39 to 44 amino acids long. A similar but soluble A beta (sA beta) has been identified in plasma, cerebrospinal fluid (CSF) and cell supernatants, indicating that it is a normal protein. We report here that sA beta in normal human plasma and CSF is complexed to high density lipoprotein (HDL) 3 and very high density lipoprotein (VHDL). Biotinylated synthetic peptide A beta 1-40 was traced in normal human plasma in in vitro experiments. Both tracer biotin-labeled A beta 1-40 and native sA beta were specifically recovered in HDL3 and VHDL as it was assessed in immunoprecipitation experiments of purified plasma lipoproteins and lipoprotein depleted plasma. This fact prompted us to ascertain whether the interaction of sA beta with HDL does occur in normal human CSF in vivo. For this purpose normals human CSF was fractionated by means of sequential flotation ultracentrifugation. The presence of sA beta in the resulting lipoprotein fractions as well as in the lipoprotein depleted CSF was analysed by immunoblot analysis, electron and immune-electron microscopy and native size exclusion chromatography. Immunoblot analysis with 6E10 monoclonal anti-A beta antibodies revealed sA beta association with all HDL subspecies of CSF, primarily HDL3 and VHDL and immunoelectron microscopy confirmed an association of sA beta with CSF-HDL particles of 16,8 + 3,2 nm. Native size exclusion chromatography followed by immunoblot analysis with antibodies against A beta and different apolipoproteins indicated an association of sA beta with HDL complexes of (-)200 kDa molecular weight. Soluble A beta association with HDL3 and VHDL may be involved in maintaining the solubility of A beta in biological fluids and points to a possible role of lipoproteins and lipoprotein lipid in the biology of aminoloidogenic peptides.