Oligomerization and neurotoxicity of the amyloid ADan peptide implicated in familial Danish dementia.
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.
Gibson
Gillian
G
Department of Basic Medical Sciences, St George's Hospital Medical School, London, UK.
Gunasekera
Nicola
N
Lee
Maria
M
Lelyveld
Victor
V
El-Agnaf
Omar M A
OM
Wright
Andrew
A
Austen
Brian
B
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000682:Amyloid / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity* / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D045744:Cell Line, Tumor; D003704:Dementia / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity / Q000648:ultrastructure
D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; D016229:Amyloid beta-Peptides; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments