Familial British
dementia, a rare autosomal dominant
neurodegenerative disorder, shares features with
Alzheimer's disease, including
amyloid plaque deposits, neurofibrillary tangles, neuronal loss,progressive
dementia, but clinically presents with additional physical defects [1,2]. A mutation in the
termination codon of the BRI gene produces a BRI precursor
protein 11
amino acids longer than the wild-type
protein [3,4]. Mutant and wild-type precursor
proteins both may undergo
furin cleavage between residues 243 and 244, producing a
peptide of 34
amino acids in the case of ABri and 23
amino acids long in the case of the wild type
peptide. The ABri 4kDa
peptide is the main component of the
amyloid deposits found in familial British
dementia brains. A decamer duplication in the 3- region of the BRI gene originates the
peptide Adan that is associated with
dementia in
Familial Danish dementia (FDD), similar to
BDD clinically, but with additional hearing and eyesight loss [5]. The resulting reading frame is extended to 277
amino acid residues, and cleavage by
furin releases a
peptide of 34 residues, which is identical to Abri and WT in its N-terminal 22-residues, but contains a distinct C-terminal 10 residues composed of mainly hydrophobic residues. Here we demonstrate that C-terminal extensions of Abri and Adan are required to elongate initially-formed dimers to neurotoxic soluble oligomers and fibrils. In contrast, the shorter wild-type
peptide does not aggregate under the same conditions and is not toxic. Conformational analyses indicate triple-beta-sheet structures. Soluble nonfibrillar oligomers of oxidised ABri and reduced Adan were observed in
solution (pH7.4) of
peptides prior to the appearance of mature fibrils.