Non-fibrillar oligomeric species of the amyloid ABri peptide, implicated in familial British dementia, are more potent at inducing apoptotic cell death than protofibrils or mature fibrils

Omar Ali El-Agnaf, Sidhartha Nagala, Bhroma P. Patel, Brian M. Austen

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Familial British dementia (FBD) is an autosomal dominant neurodegenerative disorder, with biochemical and pathological similarities to Alzheimer's disease. FBD is associated with a point mutation in the stop codon of the BRI gene. The mutation extends the length of the wild-type protein by 11 amino acids, and following proteolytic cleavage, results in the production of a cyclic peptide (ABri) 11 amino acids longer than the wild-type (WT) peptide produced from the normal gene BRI. ABri was found to be the main component of amyloid deposits in FBD brains. However, pathological examination of FBD brains has shown the presence of ABri as non-fibrillar deposits as well as amyloid fibrils. Taken together, the genetic, pathological and biochemical data support the hypothesis that ABri deposits play a central role in the pathogenesis of FBD. Here we report that ABri, but not WT peptide, can oligomerise and form amyloid-like fibrils. We show for the first time that ABri induces apoptotic cell death, whereas WT is not toxic to cells. Moreover, we report the novel findings that non-fibrillar oligomeric species of ABri are more toxic than protofibrils and mature fibrils. These findings provide evidence that non-fibrillar oligomeric species are likely to play a critical role in the pathogenesis of FBD and suggest that a similar process may also operate in other neurodegenerative diseases.

Original languageEnglish
Pages (from-to)157-168
Number of pages12
JournalJournal of Molecular Biology
Volume310
Issue number1
DOIs
Publication statusPublished - 29 Jun 2001
Externally publishedYes

Fingerprint

Abrus
Amyloid
Cell Death
Peptides
Poisons
Neurodegenerative Diseases
Amino Acids
Cyclic Peptides
Terminator Codon
Amyloid Plaques
Brain
Familial British Dementia
Point Mutation
Genes
Molecular Biology
Alzheimer Disease
Mutation

Keywords

  • Alzheimer's disease
  • Amyloid
  • Familial British dementia
  • Fibrillogenesis
  • Neurotoxicity

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Non-fibrillar oligomeric species of the amyloid ABri peptide, implicated in familial British dementia, are more potent at inducing apoptotic cell death than protofibrils or mature fibrils. / Ali El-Agnaf, Omar; Nagala, Sidhartha; Patel, Bhroma P.; Austen, Brian M.

In: Journal of Molecular Biology, Vol. 310, No. 1, 29.06.2001, p. 157-168.

Research output: Contribution to journalArticle

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abstract = "Familial British dementia (FBD) is an autosomal dominant neurodegenerative disorder, with biochemical and pathological similarities to Alzheimer's disease. FBD is associated with a point mutation in the stop codon of the BRI gene. The mutation extends the length of the wild-type protein by 11 amino acids, and following proteolytic cleavage, results in the production of a cyclic peptide (ABri) 11 amino acids longer than the wild-type (WT) peptide produced from the normal gene BRI. ABri was found to be the main component of amyloid deposits in FBD brains. However, pathological examination of FBD brains has shown the presence of ABri as non-fibrillar deposits as well as amyloid fibrils. Taken together, the genetic, pathological and biochemical data support the hypothesis that ABri deposits play a central role in the pathogenesis of FBD. Here we report that ABri, but not WT peptide, can oligomerise and form amyloid-like fibrils. We show for the first time that ABri induces apoptotic cell death, whereas WT is not toxic to cells. Moreover, we report the novel findings that non-fibrillar oligomeric species of ABri are more toxic than protofibrils and mature fibrils. These findings provide evidence that non-fibrillar oligomeric species are likely to play a critical role in the pathogenesis of FBD and suggest that a similar process may also operate in other neurodegenerative diseases.",
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