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Secreted Glypican Binds to the Amyloid Precursor Protein of Alzheimer's Disease (APP) and Inhibits APP-induced Neurite Outgrowth
journal contribution
posted on 2023-05-17, 07:00 authored by Williamson, TG, Mok, SS, Henry, A, Cappai, R, Lander, AD, Nurcombe, V, Beyreuther, K, Masters, CL, David SmallDavid SmallThe 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 APP695 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.
History
Publication title
Journal of Biological ChemistryVolume
271Issue
49Pagination
31215-31221ISSN
0021-9258Department/School
Menzies Institute for Medical ResearchPublisher
Amer Soc Biochemistry Molecular Biology IncPlace of publication
9650 Rockville Pike, Bethesda, USA, Md, 20814-3996Repository Status
- Restricted