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

Familial British dementia (FBD) is an autosomal dominant neurodegenerative disorder, with biochemical and pathological similarities to Alzheimer's disease. FED 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 wildtype (WT) peptide produced from the normal gene BRI. ABri was found to be the main component of amyloid deposits in FED brains. However, pathological examination of FED 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 FED. Here we report that ABri, but not WT peptide, can oligomerise and form amyloidlike 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 nonfibrillar oligomeric species are likely to play a critical role in the pathogenesis of FED and suggest that a similar process may also operate in other neurodegenerative diseases. (C) 2001 Academic Press.