The amyloid beta protein in normal human plasma and cerebrospinal fluid is associated with high density lipoproteins

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 (Aβ), a unique peptide 39 to 44 amino acids long. A similar but soluble Aβ (sAβ) has been identified in plasma, cerebrospinal fluid (CSF) and cell supernatants, indicating that it is a normal protein. We report here that sAβ in normal human plasma and CSF is complexed to high density lipoprotein (HDL) 3 and very high density lipoprotein (VHDL). Biotinylated synthetic peptide Aβ1-40 was traced in normal human plasma in in vitro experiments. Both tracer biotin-labeled Aβ1-40 and native sAβ were specifically recovered in HDL3 and VHDL as it was assessed in immunoprecipitation experiments of purified plasmalipoproteins and lipoprotein depleted plasma.This fact prompted us to ascertain whether the interaction of sAβ 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 sAβ 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-Aβ antibodies revealed sAβ association with all HDL subspecies of CSF, primarily HDL3 and VHDL and immunoelectron microscopy confirmed an association of sAβ with CSF-HDL particles of 16,8 + 3,2 nm. Native size exclusion chromatography followed by immunoblot analysis with antibodies against Aβ and different apolipoproteins indicated an association of sAβ with HDL complexes of ∼200 kDa molecular weight. Soluble Aβ association with HDL3 and VHDL may be involved in maintaining the solubility of Aβ in biological fluids and points to apossible role of lipoproteins and lipoprotein lipid in the biology of aminoloidogenic peptides.