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Volume 271, Number 49,
Issue of December 6, 1996
pp. 31215-31221
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
Secreted Glypican Binds to the Amyloid Precursor Protein of
Alzheimer's Disease (APP) and Inhibits APP-induced Neurite
Outgrowth
(Received for publication, May 8, 1996, and in revised form, September 5, 1996)
Timothy G.
Williamson
,
Su San
Mok
,
Anna
Henry
,
Roberto
Cappai
,
Arthur D.
Lander
¶
,
Victor
Nurcombe
**
,
Konrad
Beyreuther

,
Colin L.
Masters
and
David H.
Small
From the Department of Pathology, the ** Department of
Anatomy and Cell Biology, the University of Melbourne and the
Mental Health Research Institute of Victoria, Parkville,
Victoria 3052, Australia, the ¶ Department of Developmental and
Cell Biology, University of California,
Irvine, California 92717-2300, and the
 Center for Molecular Biology, University of
Heidelberg, D-6900 Heidelberg, Federal Republic of Germany
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 substrate-bound 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.

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Copyright © 1996 by the American Society for Biochemistry and Molecular Biology.
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