Development of a proteolytically stable retro-inverso peptide inhibitor of β-amyloid oligomerization as a potential novel treatment for Alzheimers Disease

Mark Taylor, Susan Moore, Jennifer Mayes, Edward Parkin, Marten Beeg, Mara Canovi, Marco Gobbi, David M A Mann, David Allsop

Research output: Contribution to journalArticlepeer-review

Abstract

The formation of β-amyloid (Aβ) deposits in the brain is likely to be a seminal step in the development of Alzheimers disease. Recent studies support the hypothesis that Aβ soluble oligomers are toxic to cells and have potent effects on memory and learning. Inhibiting the early stages of Aβ aggregation could, therefore, provide a novel approach to treating the underlying cause of AD. We have designed a retro-inverso peptide (RI-OR2, H 2N-r→G→k→l→v→f→f→G→r-Ac), based on a previously described inhibitor of Aβ oligomer formation (OR2, H2N-R-G-K-L-V-F-F-G-R-NH2). Unlike OR2, RI-OR2 was highly stable to proteolysis and completely resisted breakdown in human plasma and brain extracts. RI-OR2 blocked the formation of Aβ oligomers and fibrils from extensively deseeded preparations of Aβ(1-40) and Aβ(1-42), as assessed by thioflavin T binding, an immunoassay method for Aβ oligomers, SDS-PAGE separation of stable oligomers, and atomic force microscopy, and was more effective against Aβ(1-42) than Aβ(1-40). In surface plasmon resonance experiments, RI-OR2 was shown to bind to immobilized Aβ(1-42) monomers and fibrils, with an apparent Kd of 9-12 μM, and also acted as an inhibitor of Aβ(1-42) fibril extension. In two different cell toxicity assays, RI-OR2 significantly reversed the toxicity of Aβ(1-42) toward cultured SH-SY5Y neuroblastoma cells. Thus, RI-OR2 represents a strong candidate for further development as a novel treatment for Alzheimers disease.

Original languageEnglish
Pages (from-to)3261-3272
Number of pages12
JournalBiochemistry
Volume49
Issue number15
DOIs
Publication statusPublished - Apr 20 2010

ASJC Scopus subject areas

  • Biochemistry

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