Interaction between Alzheimer's disease βA4 precursor protein (APP) and the extracellular matrix: Evidence for the participation of heparan sulfate proteoglycans

The interaction between the Alzheimer amyloid precursor protein (APP) and an intact extracellular matrix (ECM), matrigel, obtained from Engelbreth-Holm-Swarm tumors was evaluated. Based on quantitative analyses of the binding data obtained from solid phase binding assays, two binding sites on the ECM were identified for ¹²⁵I]-APP (with apparent Kd₁ of 1.0 × 10 ^?11 M and Kd₂ of 1.6 × 10 ^?9 M respectively). Over 70% of ¹²⁵I]-APP was displaced by heparin and N-desulfated heparin but not by chondroitin sulfate. Pretreatment of matrigel with heparitinase decreased the binding of ¹²⁵I]-APP by 80%. β-amyloid peptides (residues 1–40, 1–28, and 1–16) containing a heparin binding domain also displaced 80% of bound ¹²⁵I]-APP, which was totally displaced by intact APP. The binding of ¹²⁵I]-APP to matrigel increased by 210% with a decrease in the pH. These observations suggest that ¹²⁵I]-APP interacts mainly with heparan sulfate proteoglycan present in the ECM. The binding of ¹²⁵I]-APP to individual ECM components was also analyzed. ¹²⁵I]-APP was found to bind laminin and collagen type IV but not fibronectin. However, when these ECM constituents were combined, the extent of APP-binding decreased significantly, to levels comparable to those obtained with intact matrigel, suggesting that multiple interactions may occur between ECM constituents and ¹²⁵I]-APP. The results are discussed in terms of APP function and amyloidogenesis. J. Cell. Biochem. 65:145–158. © 1997 Wiley-Liss, Inc.