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 nonfibrillar 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.

No abstract

The underlying cause of Alzheimer's disease is thought to be the aggregation of monomeric beta-amyloid (Abeta), through a series of toxic oligomers, which forms the mature amyloid fibrils that accumulate at the center of senile plaques. It has been reported that L-(-)-nicotine prevents Abeta aggregation and toxicity, and inhibits senile plaque formation. Previous NMR studies have suggested that this could be due to the specific binding of L-(-)-nicotine to histidine residues (His6, His13, and His14) in the peptide. Here, we have looked at the effects of both of the L-(-) and D-(+) optical enantiomers of nicotine on the aggregation and cytotoxicity of Abeta(1-40). Surprisingly, both enantiomers inhibited aggregation of the peptide and reduced the toxic effects of the peptide on cells. In NMR studies with Abeta(1-40), both enantiomers of nicotine were seen to interact with the three histidine residues. Overall, our data indicate that nicotine can delay Abeta fibril formation and maintain a population of less toxic Abeta species. This effect cannot be due to a highly specific binding interaction between nicotine and Abeta, as previously thought, but could be due instead to weaker, relatively nonspecific binding, or to the antioxidant or metal chelating properties of nicotine. D-(+)-nicotine, being biologically much less active than L-(-)-nicotine, might be a useful therapeutic agent.

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.

This is a repository copy of Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study..