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A Heparin-binding Domain in the Amyloid Protein Precursor of Alzheimer's Disease Is Involved in the Regulation of Neurite Outgrowth

Citation

Small, DH and Nurcombe, V and Reed, G and Clarris, H and Moir, R and Beyreuther, K and Masters, CL, A Heparin-binding Domain in the Amyloid Protein Precursor of Alzheimer's Disease Is Involved in the Regulation of Neurite Outgrowth, Journal of Neuroscience, 14, (4) pp. 2117-2127. ISSN 0270-6474 (1994) [Refereed Article]

Abstract

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, substratumbound 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-l 10) 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 7251-labeled APP to heparin (IC,, = 10m7 M). The peptide blocked the effect of APP on neurite outgrowth (IC,, = lo-’ 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.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Neurosciences not elsewhere classified
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Neurodegenerative Disorders Related to Ageing
Author:Small, DH (Professor David Small)
ID Code:71707
Year Published:1994
Web of Science® Times Cited:304
Deposited By:Menzies Institute for Medical Research
Deposited On:2011-08-02
Last Modified:2011-08-02
Downloads:0

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