. Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism. Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9758-63. PubMed.

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  1. This is a very nice study that brings together the use of several different approaches—mathematical modeling of protein polymerization, reliable assay systems to measure kinetics of Aβ aggregation, and innovative use of radiolabeled Aβ and size-exclusion chromatography. The conclusions reached build on a range of earlier findings including prior in-vitro data that also hinted at the importance of secondary nucleation (e.g., Wogulis et al., 2005; Jan et al., 2008; Jeong et al., 2013), and speculation that interaction between plaques (fibrils) and soluble Aβ is critical for toxicity (Koffie et al., 2009; Spires et al., 2009; McDonald et al., 2010; Esparaza et al., 2012). The most impressive aspects of this study are the quality of the kinetic data and the rigor of the analyses, both of which indicate that amyloid fibrils provide a catalytic surface for the generation of Aβ oligomers.

    After thoughtfully considering the major factors believed to be important in Aβ aggregation (monomer concentration, nucleus formation, fibril elongation, and fibril fragmentation), the authors generated three predictive models and then tested them versus experimentally determined data. Thus, the outcome largely hinged on the use of a highly reproducible assay to monitor aggregation (Hellstrand et al., 2009). By examining the aggregation process under different shear conditions, they demonstrated that fragmentation of fibrils (as predicted) can also influence aggregation kinetics. Then, by seeding radiolabeled Aβ monomer with preformed unlabeled Aβ fibrils, they found that fibrils can catalyze the formation of oligomers, but that “ThT transparent” oligomers never account for more than 1 percent of the total mass of Aβ present. From Figure 4B, these oligomers appear to elute in or near to the void of a Superdex 75 column and therefore could be consistent with polydispersed prefibrillar assemblies such as protofibrils (Walsh et al., 1999; Harper et al., 1999) or ADDLs (Lambert et al., 1998; Hepler et al., 2006).

    Finally, the authors present data suggesting that oligomers are biologically active. Although this is what one would expect, these experiments are the least solid part of the paper. Since it is not clear if these oligomers are stable during prolonged incubation and the toxicity assays were measured over 24 hours, it will be important to characterize oligomer activity using more rapid (and disease-relevant) assays. It will be similarly important to gain information about the structure of these oligomers and how they compare with assemblies isolated from human brain. Translating the lessons learned from this carefully controlled model to the chaos of the diseased brain will be challenging, not least because in the brain there are multiple Aβ peptides of different primary sequence and an abundance of surfaces on which to interact. Nonetheless, as an old-fashioned reductionist, I’m hopeful this study will help us inch a little closer to the worthy goal of preventing the formation (or neutralizing the effects) of toxic assemblies of Aβ.

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