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

Research output: Contribution to journalArticle

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

Fingerprint

Oligomerization
Amyloid
Deposits
Peptides
Genes
Poisons
Neurodegenerative Diseases
Neurodegenerative diseases
Cerebral Amyloid Angiopathy
Oligomers
Daucus carota
Electron microscopy
Atomic Force Microscopy
Amyloid Plaques
Codon
Gels
Cells
Spectroscopy
Gel Chromatography
Spectrum Analysis

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.

Oligomerization and neurotoxicity of the amyloid ADan peptide implicated in familial Danish dementia. / Gibson, Gillian; Gunasekera, Nicola; Lee, Maria; Lelyveld, Victor; Ali El-Agnaf, Omar; Wright, Andrew; Austen, Brian.

In: Journal of Neurochemistry, Vol. 88, No. 2, 01.2004, p. 281-290.

Research output: Contribution to journalArticle

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, vol. 88, no. 2, pp. 281-290.
Gibson, Gillian ; Gunasekera, Nicola ; Lee, Maria ; Lelyveld, Victor ; Ali El-Agnaf, Omar ; Wright, Andrew ; Austen, Brian. / Oligomerization and neurotoxicity of the amyloid ADan peptide implicated in familial Danish dementia. In: Journal of Neurochemistry. 2004 ; Vol. 88, No. 2. pp. 281-290.
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