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

1997; Wiley; Volume: 65; Issue: 2 Linguagem: Inglês

10.1002/(sici)1097-4644(199705)65

1097-4644

Jorge O. Cáceres, Enrique Brandan,

Amyloidosis: Diagnosis, Treatment, Outcomes

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.