Abstract
The accumulation of senile plaques composed of amyloid β (Aβ) fibrils is a hallmark of Alzheimer's disease, although prefibrillar oligomeric species are believed to be the primary neurotoxic congeners in the pathogenesis of Alzheimer's disease. Uncertainty regarding the mechanistic relationship between Aβ oligomer and fibril formation and the cytotoxicity of these aggregate species persists. β-Turn formation has been proposed to be a potential rate-limiting step during Aβ fibrillogenesis. The effect of turn nucleation on Aβ self-assembly was probed by systematically replacing amino acid pairs in the putative turn region of Aβ (residues 24-27) with d-ProGly (DPG), an effective turn-nucleating motif. The kinetic, thermodynamic, and cytotoxic effects of these mutations were characterized. It was found that turn formation dramatically accelerated Aβ fibril self-assembly dependent on the site of turn nucleation. The cytotoxicity of the three DPG-containing Aβ variants was significantly lower than that of wild-type Aβ40, presumably due to decreased oligomer populations as a function of a more rapid progression to mature fibrils; oligomer populations were not eliminated, however, suggesting that turn formation is also a feature of oligomer structures. These results indicate that turn nucleation is a critical step in Aβ40 fibril formation.
Original language | English (US) |
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Pages (from-to) | 315-328 |
Number of pages | 14 |
Journal | Journal of Molecular Biology |
Volume | 421 |
Issue number | 2-3 |
DOIs | |
State | Published - Aug 10 2012 |
Bibliographical note
Funding Information:We thank Karen Bentley (University of Rochester Medical Center Electron Microscope Research Core) for assistance with TEM experiments. This work was supported by a DuPont Young Professor Award to B.L.N. and by the Alzheimer's Association ( NIRG-08-90797 ). This work was also supported by National Institutes of Health grants P30ES01247 and T32ES07026 (to S.E.L. and L.A.O.). Mass spectroscopy instrumentation was partially supported by US National Science Foundation grants CHE-0840410 and CHE-0946653 .
Keywords
- Alzheimer's disease
- amyloid β
- fibril self-assembly
- turn nucleation
- β-hairpin