A structure-toxicity study of Aß42 reveals a new anti-parallel aggregation pathway.
Amyloid beta (Aβ) peptides produced by APP cleavage are central to the pathology of Alzheimer's disease. Despite widespread interest in this issue, the relationship between the auto-assembly and toxicity of these peptides remains controversial. One intriguing feature stems from their capacity to form anti-parallel ß-sheet oligomeric intermediates that can be converted into a parallel topology to allow the formation of protofibrillar and fibrillar Aβ. Here, we present a novel approach to determining the molecular aspects of Aß assembly that is responsible for its in vivo toxicity. We selected Aß mutants with varying intracellular toxicities. In vitro, only toxic Aß (including wild-type Aß42) formed urea-resistant oligomers. These oligomers were able to assemble into fibrils that are rich in anti-parallel ß-sheet structures. Our results support the existence of a new pathway that depends on the folding capacity of Aß .
Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université Bordeaux Segalen, Bordeaux, France.
Hélène
H
Vignaud
Claude
C
Bobo
Ioan
I
Lascu
Karin Margareta
KM
Sörgjerd
Tamotsu
T
Zako
Mizuo
M
Maeda
Benedicte
B
Salin
Sophie
S
Lecomte
Christophe
C
Cullin
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002942:Circular Dichroism; D046529:Microscopy, Electron, Transmission; D016716:PC12 Cells; D051381:Rats
D016229:Amyloid beta-Peptides