Secreted Glypican Binds to the Amyloid Precursor Protein of Alzheimer's Disease (APP) and Inhibits APP-induced Neurite Outgrowth

Abstract

The amyloid precursor protein (APP) of Alzheimer's disease has been shown to stimulate neurite outgrowth in vitro. The effect of APP on neurite outgrowth can be enhanced if APP is presented to neurons in substratebound form, in the presence of heparan sulfate proteoglycans. To identify specific heparan sulfate proteoglycans that bind to APP, conditioned medium from neonatal mouse brain cells was subjected to affinity chromatography with recombinant APP 695 as a ligand. Glypican bound strongly to the APP affinity column. Purified glypican bound to APP with an equilibrium dissociation constant of 2.8 nM and inhibited APP-induced neurite outgrowth from chick sympathetic neurons. The effect of glypican was specific for APP, as glypican did not inhibit laminin-induced neurite outgrowth. Furthermore, treatment of cultures with 4-methylumbelliferyl-␤-D-xyloside, a competitive inhibitor of proteoglycan glycanation, inhibited APP-induced neurite outgrowth but did not inhibit laminin-induced neurite outgrowth. This result suggests that endogenous proteoglycans are required for substrate-bound APP to stimulate neurite outgrowth. Secreted glypican may act to inhibit APP-induced neurite outgrowth in vivo by competing with endogenous proteoglycans for binding to APP.Alzheimer's disease is a progressive dementia that is characterized by neuronal degeneration, synaptic loss, and the deposition of amyloid fibrils in the brain. The major constituent of the amyloid is the A␤ protein (1, 2), which is derived from the amyloid precursor protein (APP).

Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex

“…Our findings on the sequence involved in E-cadherin͞PS1 binding suggest a model for PS1 binding to APP and Notch-1 receptors. In addition, cadherin is involved in cell adhesion and signaling, and APP may have similar functions (34,35). That PS1 forms complexes with the APP, Notch-1, and E-cadherin systems suggests that in addition to APP processing, PS1 FAD mutations may target other type I transmembrane protein systems, including Notch-1 and cadherins.…”

Phosphorylation of the β-Amyloid Precursor Protein at the Cell Surface by Ectocasein Kinases 1 and 2

“…The inhibition of ␤APP phosphorylation by heparin might represent a regulatory mechanism in vivo because heparin and ecto-CKs could interact in the extracellular environment. The effect of heparin on the biological functions of ␤APP such as its neurite outgrowth-promoting activity (23,75) might therefore depend not only on its direct binding to ␤APP, but also on the inhibition of ␤APP phosphorylation.…”

Reversible Regulation of Tissue Factor–Induced Coagulation by Glycosyl Phosphatidylinositol–Anchored Tissue Factor Pathway Inhibitor

“…This suggests that serpins and TFPIs share some proteoglycan binding sites in the detergent-soluble fractions but that the association with detergent-insoluble microdomains is a specific property of TFPIs. Because glypican 1 has been found to bind to another Kunitz-type inhibitor, the amyloid precursor protein inhibitor, 35 one may speculate that association with glycosphingolipid-rich microdomains is a specific property of Kunitz-type protease inhibitors.…”