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Published Online
on May 10, 2002

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The Journal of Neuroscience, 2002, 22:RC221:1-5

RAPID COMMUNICATION
Alzheimer's -Amyloid Peptides Compete for Insulin Binding to the Insulin Receptor

Ling Xie^{1, 3}, Erik Helmerhorst¹, Kevin Taddei³, Brian Plewright¹, Wilhelm van Bronswijk², and Ralph Martins³

¹ School of Biomedical Sciences and ² Department of Applied Chemistry, Western Australian Biomedical Research Institute, Curtin University of Technology, Bentley, Western Australia, 6102 Australia, and ³ Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, University Department of Surgery, University of Western Australia, Nedlands, Western Australia, 6009 Australia

The amyloid- (A) peptide is neurotoxic and associated with the pathology of Alzheimer's disease (AD). We investigated the effect of A peptides on insulin binding to the insulin receptor because it is known that (1) A and insulin are both amyloidogenic peptides sharing a common sequence recognition motif, (2) A and insulin are substrates for the same insulin degrading enzyme, and (3) impaired glucose metabolism is a characteristic event in the pathology of AD. We discovered that A_1-40 and A_1-42, the main physiological forms, reduced insulin binding and receptor autophosphorylation. The reduction in binding was caused by a decrease in the affinity of insulin binding to the insulin receptor. This reduction was independent of the receptor concentration. The reverse, control peptide A_40-1 did not reduce insulin binding or insulin receptor autophosphorylation. These results demonstrate that A is a direct competitive inhibitor of insulin binding and action. We speculate that the increased levels of A in Alzheimer's disease may be linked to the associated insulin resistance that has been observed previously in this disease.

Key words: amyloid- peptide; insulin binding; insulin receptors; Scatchard analysis; Alzheimer's disease; diabetes

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Copyright © Society for Neuroscience  0270-6474//$05.00/0

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