SECRETED GLYPICAN BINDS TO THE AMYLOID PRECURSOR PROTEIN OF ALZHEIMERS-DISEASE (APP) AND INHIBITS APP-INDUCED NEURITE OUTGROWTH

The amyloid precursor protein (APP) of Alzheimer's disease has been sh own to stimulate neurite outgrowth in vitro. The effect of APP on neur ite outgrowth can be enhanced if APP is presented to neurons in substr ate-bound form, in the presence of heparan sulfate proteog lycans. To identify specific heparan sulfate proteoglycans that bind to APP, cond itioned medium from neonatal mouse brain cells was subjected to affini ty chromatography with recombinant APP(695) as a ligand, Glypican boun d 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 o f glypican was specific for APP, as glypican did not inhibit laminin-i nduced neurite outgrowth, Furthermore, treatment of cultures with 4-me thylumbelliferyl-beta-D-xyloside, a competitive inhibitor of proteogly can glycanation, inhibited APP-induced neurite outgrowth but did not i nhibit laminin-induced neurite outgrowth, This result suggests that en dogenous proteoglycans are required for substrate-bound APP to stimula te neurite outgrowth, Secreted glypican may act to inhibit APP-induced neurite outgrowth in vivo by competing with endogenous proteoglycans for binding to APP.