. Structural variation in amyloid-β fibrils from Alzheimer's disease clinical subtypes. Nature. 2017 Jan 12;541(7636):217-221. Epub 2017 Jan 4 PubMed.


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  1. "Amplification bias" is certainly an issue that needs to be considered when fibril structures from brain tissue are amplified by seeded growth. Certain structures may self-propagate more efficiently than others, depending on the precise details of the experimental conditions for seeded growth. When many successive rounds of seeded growth are used, it is even possible to "purify" a single structure from an initially heterogeneous mixture, as we have demonstrated in earlier in vitro studies of fibril growth and fibril structure.

    To minimize this potential problem in the experiments with brain tissue discussed above, we used a single amplification step, first sonicating our brain extract vigorously so that all Aβ fibrils in the extract were broken into short fragments, and then adding a single aliquot of solubilized Aβ peptide to the sonicated extract. TEM images were recorded after four hours, showing long fibrils that grew from sonicated seeds when AD brain tissue was used (but not when non-AD control tissue was used).

    Despite the possible remaining effects of amplification bias, we did observe a statistically significant difference in ssNMR data between rAD and tAD tissue samples, and real differences in ssNMR spectra of fibrils derived from different tissue samples. If anything, one would expect such differences to be reduced by amplification bias.

    View all comments by Robert Tycko

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