Oligomerization and neurotoxicity of the amyloid ADan peptide implicated in familial Danish dementia

Gillian Gibson, Nicola Gunasekera, Maria Lee, Victor Lelyveld, Omar Ali El-Agnaf, Andrew Wright, Brian Austen

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28 Citations (Scopus)

Abstract

Familial Danish dementia (FDD) is a rare neurodegenerative disorder, which is pathologically characterized by widespread cerebral amyloid angiopathy, parenchymal protein deposits and neurofibrillary degeneration. FDD is associated with mutation in the BRI gene. In FDD a decamer duplication between codons 265 and 266 in the 3′ region of the BRI gene originates an amyloid peptide named ADan, 11 residues longer than the wild-type peptide produced from the normal BRI gene. ADan deposits have been found widely distributed in the CNS of FDD cases. The deposits of ADan are predominantly non-fibrillar aggregates. We show here that synthetic ADan forms oligomers in vitro, seen by Tricine-PAGE and gel filtration, and higher aggregates, which are seen by atomic force spectroscopy and electron microscopy as carrot-shaped objects that bunch together. Here we report that oligomeric ADan is toxic to neuronal cell lines. We find that the soluble non-fibrillar oligomeric species of both the reduced and oxidized forms of ADan are toxic. These results support the idea that the non-fibrillar soluble aggregates are the pathogenic species, which may play a central role in the pathogenesis of FDD, and imply that similar mechanism may also be involved in other neurodegenerative diseases associated with amyloid deposits.

Original languageEnglish
Pages (from-to)281-290
Number of pages10
JournalJournal of Neurochemistry
Volume88
Issue number2
Publication statusPublished - Jan 2004
Externally publishedYes

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Keywords

  • ADan
  • Amyloid
  • BRI
  • Danish dementia
  • Neurotoxicity
  • Oligomers

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Gibson, G., Gunasekera, N., Lee, M., Lelyveld, V., Ali El-Agnaf, O., Wright, A., & Austen, B. (2004). Oligomerization and neurotoxicity of the amyloid ADan peptide implicated in familial Danish dementia. Journal of Neurochemistry, 88(2), 281-290.