Specific compositions of amyloid-beta peptides as the determinant of toxic beta-aggregation.
Alzheimer's disease (AD) may be caused by toxic aggregates formed from amyloid-beta (Abeta) peptides. By using Thioflavin T, a dye that specifically binds to beta-sheet structures, we found that highly toxic forms of Abeta-aggregates were formed at the initial stage of fibrillogenesis, which is consistent with recent reports on Abeta oligomers. Formation of such aggregates depends on factors that affect both nucleation and elongation. As reported previously, addition of Abeta42 systematically accelerated the nucleation of Abeta40, most likely because of the extra hydrophobic residues at the C terminus of Abeta42. At Abeta42-increased specific ratio (Abeta40: Abeta42 = 10: 1), on the other hand, not only accelerated nucleation but also induced elongation were observed, suggesting pathogenesis of early-onset AD. Because a larger proportion of Abeta40 than Abeta42 was still required for this phenomenon, we assumed that elongation does not depend only on hydrophobic interactions. Without any change in the C-terminal hydrophobic nature, elongation was effectively induced by mixing wild type Abeta40 with Italian variant Abeta40 (E22K) or Dutch variant (E22Q). We suggest that Abeta peptides in specific compositions that balance hydrophilic and hydrophobic interactions promote the formation of toxic beta-aggregates. These results may introduce a new therapeutic approach through the disruption of this balance.
Yoshiike
Yuji
Y
Laboratory for Alzheimer's Disease, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
Chui
De-Hua
DH
Akagi
Takumi
T
Tanaka
Nobuo
N
Takashima
Akihiko
A
D000544:Alzheimer Disease / Q000209:etiology*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D052160:Benzothiazoles; D002460:Cell Line; D019281:Dimerization; D014644:Genetic Variation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics; D055672:Static Electricity; D013844:Thiazoles
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C009462:thioflavin T