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Journal of Neuroscience, Vol 14, 2117-2127, Copyright © 1994 by Society for Neuroscience
A heparin-binding domain in the amyloid protein precursor of Alzheimer's disease is involved in the regulation of neurite outgrowth
DH Small, V Nurcombe, G Reed, H Clarris, R Moir, K Beyreuther and CL Masters
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
The amyloid protein precursor (APP) of Alzheimer's disease is synthesized
as an integral transmembrane protein that is released from cells in culture
following proteolytic cleavage. The function of released APP is not known,
although there is evidence that the protein may bind to components of the
extracellular matrix (ECM). In the present study, substratum-bound APP
stimulated neurite outgrowth in cultures of chick sympathetic and mouse
hippocampal neurons. This effect was dependent upon the presence of
substratum-bound heparan sulfate proteoglycans (HSPG). The effect of APP on
neurite outgrowth was comparable to that of laminin. A 14 K N-terminal
fragment of APP was found to bind heparin and a region close to the
N-terminus of APP (residues 96-110) identified as a potential
heparin-binding domain based on secondary structure predictions and
molecular modeling. Mutagenesis of three basic residues (lysine-99,
arginine-100, and arginine-102) resulted in a recombinant protein (APPhep)
with decreased heparin-binding capacity. A peptide homologous to the
heparin-binding domain was synthesized and found to bind strongly to
heparin and to inhibit binding of 125I-labeled APP to heparin (IC50
approximately 10(- 7) M). The peptide blocked the effect of APP on neurite
outgrowth (IC50 approximately 10(-7) M), whereas two other peptides
homologous to other domains in APP had no effect. The results indicate that
the binding of APP to HSPG in the ECM may stimulate the effects of APP on
neurite outgrowth.
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