Fibulin-1 binds the amino-terminal head of β-amyloid precursor protein and modulates its physiological function
Article first published online: 20 DEC 2001
Journal of Neurochemistry
Volume 76, Issue 5, pages 1411–1420, March 2001
How to Cite
Ohsawa, I., Takamura, C. and Kohsaka, S. (2001), Fibulin-1 binds the amino-terminal head of β-amyloid precursor protein and modulates its physiological function. Journal of Neurochemistry, 76: 1411–1420. doi: 10.1046/j.1471-4159.2001.00144.x
- Issue published online: 20 DEC 2001
- Article first published online: 20 DEC 2001
- Received June 6, 2000; revised manuscript received October 17, 2000; accepted October 30, 2000.
- Alzheimer's disease;
- amyloid precursor protein;
- binding protein;
- neural stem cells;
Genetic studies have implicated amyloid precursor protein (APP) in the pathogenesis of Alzheimer's disease. While accumulating lines of evidence indicate that APP has various functions in cells, little is known about the proteins that modulate its biological activity. Toward this end, we employed a two-hybrid system to identify potential interacting factors. We now report that fibulin-1, which contains repetitive Ca2+-binding EGF-like elements, binds to APP at its amino-terminal growth factor-like domain, the region that is responsible for its neurotrophic activities. Fibulin-1 expression in the brain is confined to neurons, and is not expressed significantly by astrocytes or microglia. Direct binding of fibulin-1 to the secreted form of APP (sAPP) was demonstrated with a pull-down assay using fragments of both fibulin-1 fused with glutathione-S transferase and sAPP, produced in bacteria and yeast, respectively. The fibulin-1/sAPP heteromer was shown to form in the conditioned medium of transfected COS-7 cells. Furthermore, fibulin-1 blocks sAPP-mediated proliferation of primary cultured rat neural stem cells. These results suggest that fibulin-1 may play a significant role in modulating the neurotrophic activities of APP.