Designing peptide inhibitors for oligomerization and toxicity of Alzheimer's β-amyloid peptide

Brian M. Austen, Katerina E. Paleologou, Sumaya A.E. Ali, Mohamed M. Qureshi, David Allsop, Omar Ali El-Agnaf

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Convergent biochemical and genetic evidence suggests that the formation of β-amyloid (Aβ) deposits in the brain is an important and, probably, seminal step in the development of Alzheimer's disease (AD). Recent studies support the hypothesis that Aβ soluble oligomers are the pathogenic species that prompt the disease. Inhibiting Aβ self-oligomerization could, therefore, provide a novel approach to treating the underlying cause of AD. Here, we designed potential peptide-based aggregation inhibitors containing Aβ amino acid sequences (KLVFF) from part of the binding region responsible for Aβ self-association (residues 16-20), with RG-/-GR residues added at their N- and C-terminal ends to aid solubility. Two such peptides (RGKLVFFGR, named OR1, and RGKLVFFGR-NH2, named OR2) were effective inhibitors of Aβ fibril formation, but only one of these peptides (OR2) inhibited Aβ oligomer formation. Interestingly, this same OR2 peptide was the only effective inhibitor of Aβ toxicity toward human neuroblastoma SH-SY5Y cells. Our data support the idea that Aβ oligomers are responsible for the cytotoxic effects of Aβ and identify a potential peptide inhibitor for further development as a novel therapy for AD.

Original languageEnglish
Pages (from-to)1984-1992
Number of pages9
JournalBiochemistry
Volume47
Issue number7
DOIs
Publication statusPublished - 19 Feb 2008
Externally publishedYes

Fingerprint

Oligomerization
Amyloid
Toxicity
Peptides
Oligomers
Alzheimer Disease
Amyloid Plaques
Neuroblastoma
Solubility
Molecular Biology
Amino Acid Sequence
Brain
Deposits
Agglomeration
Association reactions
Amino Acids

ASJC Scopus subject areas

  • Biochemistry

Cite this

Designing peptide inhibitors for oligomerization and toxicity of Alzheimer's β-amyloid peptide. / Austen, Brian M.; Paleologou, Katerina E.; Ali, Sumaya A.E.; Qureshi, Mohamed M.; Allsop, David; Ali El-Agnaf, Omar.

In: Biochemistry, Vol. 47, No. 7, 19.02.2008, p. 1984-1992.

Research output: Contribution to journalArticle

Austen, Brian M. ; Paleologou, Katerina E. ; Ali, Sumaya A.E. ; Qureshi, Mohamed M. ; Allsop, David ; Ali El-Agnaf, Omar. / Designing peptide inhibitors for oligomerization and toxicity of Alzheimer's β-amyloid peptide. In: Biochemistry. 2008 ; Vol. 47, No. 7. pp. 1984-1992.
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