These results support the emerging, and now much substantiated, view that intermediates or off-pathway aggregates on the amyloid formation pathway contain anti-parallel β-sheet structures. These are, from a structural biology point of view, both similar and intriguingly different from the structure found in amyloid fibrils. There is much evidence for anti-parallel β-sheets in oligomers and numerous indications that oligomers of different peptides are built in a similar way. However, the present results represent a significant advance.

The authors report the most detailed structural analysis so far for oligomers and/or aggregation intermediates of amyloid forming peptides. Importantly, they present a basis for a "general" oligomer structure that makes sense. The cylindrin fold of oligomers with anti-parallel β-sheets and a "dry" core is a very attractive analogue to the steric zipper structure of amyloid fibrils (parallel β-sheets and a dry core). However, it needs further confirmation, preferably on peptides that are more directly disease related, such as Aβ or α-synuclein....  Read more

These results support the emerging, and now much substantiated, view that intermediates or off-pathway aggregates on the amyloid formation pathway contain anti-parallel β-sheet structures. These are, from a structural biology point of view, both similar and intriguingly different from the structure found in amyloid fibrils. There is much evidence for anti-parallel β-sheets in oligomers and numerous indications that oligomers of different peptides are built in a similar way. However, the present results represent a significant advance.

The authors report the most detailed structural analysis so far for oligomers and/or aggregation intermediates of amyloid forming peptides. Importantly, they present a basis for a "general" oligomer structure that makes sense. The cylindrin fold of oligomers with anti-parallel β-sheets and a "dry" core is a very attractive analogue to the steric zipper structure of amyloid fibrils (parallel β-sheets and a dry core). However, it needs further confirmation, preferably on peptides that are more directly disease related, such as Aβ or α-synuclein. Eisenberg’s peptide methodology for structural analysis has again proven to be a breakthrough technique for research on the structural biology of protein aggregation. Likewise, Tycko's solid-state NMR methodology keeps providing high-quality structural information on larger protein aggregates. Research such as this will potentially allow scientists to finally home in on structure-function relationships and, in particular, mechanisms of neurotoxicity. Any progress here would greatly aid drug discovery.

View all comments by Torleif Hard

Neither of these newly identified morphologies are formed in near-physiological media, including circa 1 mM of calcium and 1 mM of Mg? If they were not identified in such media, then how likely are they to form in vivo, or perhaps how likely are they to have any relevant longevity in vivo?

Spherulites of Aβ42 do form in physiological media (1) and can be identified in human brain tissue (2).

References:
1. Exley C, House E, Collingwood JF, Davidson M, Cannon D & Donald AM (2010) Spherulites of Aβ42 in vitro and in Alzheimer’s disease. Journal of Alzheimer’s Disease 20, 1159-1165. Abstract

2. House E, Jones K and Exley C (2011) Spherulites in human brain tissue are composed of beta sheets of amyloid and resemble senile plaques. Journal of Alzheimer’s Disease 25, 43-46. Abstract

View all comments by Chris Exley