Fibril formation and toxicity of the non-amyloidogenic rat amylin peptide

Milton, Nathaniel G.N. and Harris, J. Robin (2013) Fibril formation and toxicity of the non-amyloidogenic rat amylin peptide. Micron, 44. pp. 246-253. ISSN 0968-4328

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Official URL: http://dx.doi.org/10.1016/j.micron.2012.07.001

Abstract

Full-length native rat amylin 1-37 has previously been widely shown to be unable to form fibrils and to lack the toxicity of the human amylin form leading to its use as a non-amyloidogenic control peptide. A recent study has suggested that rat amylin 1-37 forms amyloidogenic ?-sheet structures in the presence of the human amylin form and suggested that this property could promote toxicity. Using TEM analysis we show here fibril formation by synthetic rat amylin 1-37 and 8-37 peptides when the lyophilized HPLC purified peptides are initially dissolved in 20 mM Tris-HCl. Dissolution of synthetic rat amylin 1-37 and 8-37 peptides in H(2)O or phosphate buffered saline failed to produce fibrils. Addition of 20 mM Tris-HCl to synthetic rat amylin 1-37 and 8-37 peptides initially dissolved in H(2)O also failed to induce fibril formation. The rat amylin fibrils have a uniform structure and bind Congo red suggesting that they are amyloid fibrils. The rat amylin fibrils also bind catalase, which could be inhibited by Amyloid-? 31-35 and a catalase amyloid-? binding domain-like peptide (R9). The rat amylin 1-37 and 8-37 fibrils are toxic in both human pancreatic islet and neuronal cell culture systems. The toxicity of rat amylin fibrils can be inhibited by an amylin receptor antagonist (AC187) and a caspase inhibitor (zVAD-fmk) in a similar manner to previous observations for human amylin toxicity. Chemically induced rat amylin fibril formation of uniform structured fibrils provides a potentially novel anti-amyloid drug discovery tool.

Item Type: Article
Subjects: University of Westminster > Science and Technology > Life Sciences, School of (No longer in use)
Depositing User: Miss Nina Watts
Date Deposited: 01 Jul 2013 14:34
Last Modified: 01 Jul 2013 14:34
URI: http://westminsterresearch.wmin.ac.uk/id/eprint/12603

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