Jucker M, Walker LC.
Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders.
Ann Neurol. 2011 Oct;70(4):532-40.
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This new study from Mathias Jucker's laboratory follows the steps of their previous work (Eisele et al., 2010) suggesting that Aβ possesses prion-like properties. Here, they refined their approach by showing that, not only did extracts from transgenic mouse brain induce amyloidosis following injection in younger animals, but also that both soluble and insoluble material (differentiated by a 100,000 x g ultracentrifugation step) derived from those extracts can reproduce this effect. There are qualitative and quantitative differences in the amyloidosis triggered by the soluble or the insoluble protein fraction. The authors report that despite constituting less than 1 percent of the total Aβ present in the extracts, the soluble fraction is capable of inducing amyloidosis. Based on proteinase K resistance assays, the authors conclude that multiple species/forms of Aβ may be necessary for inducing this effect.
Even though this result is interesting and the experiments were carefully executed, several questions readily come to mind. The biochemical characterization of the soluble and insoluble fractions compared to the initial transgenic extract is quite modest, as only monomeric Aβ levels are reported. In my opinion, it would have been more relevant to document the relative content of oligomeric Aβ molecules (dimers, trimers, Aβ*56, and annular protofibrils) present in all source material used, especially since the potential involvement of these species is suggested by the authors in the discussion. For instance, multiple Aβ antibodies could have been used to further characterize the source material (by Western blot or ELISA). Without such analyses, it is difficult to extrapolate on the nature of the assemblies responsible for the induced amyloidosis. The last presented experiment using various durations of sonication might indicate that the "soluble" molecules at play are bound to plaques. If it is the case, one would expect to see increased Aβ dimers in the fraction most sonicated, as dimers were previously shown to bind to plaques (Shankar et al., 2008). Finally, it would have been intriguing to compare the soluble fraction of the transgenic extract containing 1 percent of total Aβ with an injectate made of the insoluble fraction containing that same 1 percent of total Aβ. Doing so would allow for a better appreciation of the relative importance of the nature (oligomeric vs. fibrillar) of the Aβ species involved in these effects.