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Volume 272, Number 30, Issue of July 25, 1997 pp. 18644-18649
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Interaction of Apolipoprotein J-Amyloid -Peptide Complex with Low Density Lipoprotein Receptor-related Protein-2/Megalin
A MECHANISM TO PREVENT PATHOLOGICAL ACCUMULATION OF AMYLOID -PEPTIDE

(Received for publication, May 15, 1997)

From the Cell Biology and Anatomy Department, Medical University of South Carolina, Charleston, South Carolina 29425-2204

Apolipoprotein J (apoJ) has been shown to be the predominant amyloid -peptide (A)-binding protein in cerebrospinal fluid. We have previously demonstrated that the endocytic receptor low density lipoprotein receptor-related protein-2/megalin (LRP-2), which is expressed by choroid plexus epithelium and ependymal cells lining the brain ventricles and neural tube, binds and mediates cellular uptake of apoJ (Kounnas, M. Z., Loukinova, E. B., Stefansson, S., Harmony, J. A., Brewer, B., Strickland, D. K., and Argraves, W. S. (1995) J. Biol. Chem. 270, 13070-13075). In the present study, we evaluated the ability of apoJ to mediate binding of A_1-40-apoJ complex to LRP-2 in vitro. Immunoblot analysis showed that incubation of apoJ with A_1-40 resulted in the formation of A_1-40-apoJ complex and the inhibition of the formation of A_1-40 aggregates. Using an enzyme-linked immunosorbent assay, an estimated dissociation constant (K_d) of 4.8 nM was derived for the interaction between A_1-40 and apoJ. Enzyme-linked immunosorbent assay was also used to study the interaction of the A_1-40-apoJ complex with LRP-2. The results showed that A alone did not bind directly to LRP-2; however, when A_1-40 was combined with apoJ to form a complex, binding to LRP-2 took place. The binding interaction could be blocked by inclusion of the receptor-associated protein, an antagonist of apoJ binding to LRP-2. When LRP-2-expressing cells were given ¹²⁵I-A_1-40, cellular uptake of the radiolabeled peptide was promoted by co-incubation with apoJ. When the cells were provided purified ¹²⁵I-A_1-40-apoJ complex, the complex was internalized and degraded, and both processes were inhibited with polyclonal LRP-2 antibodies. Furthermore, chloroquine treatment inhibited the cellular degradation of the complex. The data indicate that apoJ facilitates A_1-40 binding to LRP-2 and that the receptor mediates cellular clearance of A_1-40-apoJ complex leading to lysosomal degradation of A_1-40. The findings support the possibility that LRP-2 can act in vivo to mediate clearance of the complex from biological fluids such as cerebrospinal fluid and thereby play a role in the regulation of A accumulation.

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