Interaction between Alzheimer's disease beta A4 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 x 10(-11) M and Kd2 of 1.6 x 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%. beta-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.
Cáceres
J
J
Departamento de Biología Celular y Molecular, Facultad de Ciencias Biologicas, P. Universidad Católica de Chile, Santiago, Chile.
Brandan
E
E
D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D005109:Extracellular Matrix / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007457:Iodine Radioisotopes; D007700:Kinetics; D007797:Laminin / Q000378:metabolism; D011133:Polysaccharide-Lyases / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D003094:Collagen; D004338:Drug Combinations; D005353:Fibronectins; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D007457:Iodine Radioisotopes; D007797:Laminin; D011133:Polysaccharide-Lyases; D011509:Proteoglycans; C059485:matrigel; C021349:heparitinsulfate lyase