Langer F, Eisele YS, Fritschi SK, Staufenbiel M, Walker LC, Jucker M.
Soluble Aβ seeds are potent inducers of cerebral β-amyloid deposition.
J Neurosci. 2011 Oct 12;31(41):14488-95.
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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.
Eisele YS, Obermüller U, Heilbronner G, Baumann F, Kaeser SA, Wolburg H, Walker LC, Staufenbiel M, Heikenwalder M, Jucker M.
Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis.
Science. 2010 Nov 12;330(6006):980-2.
Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ.
Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
Nat Med. 2008 Aug;14(8):837-42.
This well-designed study is an extension of the previous outstanding studies published by Jucker's group on amyloid induction in vivo. In my opinion, it represents a significant step, fortunately, in the right direction. It clearly demonstrates that soluble Aβ assemblies are potent amyloid-inducing factors. More importantly, it demonstrates that the most effective seeds are also the most conformationally dynamic and likely to bind other proteins. This study makes clever use of many well-established protocols, such as fractionation, sonication, and proteinase K digestion, to pinpoint the most effective seed, which turned out to be mainly soluble. Evolution in the amyloid field continues, and I expect that in the near future the same scenario will be demonstrated for other proteins such as synuclein and tau. The only piece of data I wish that the authors had included is information about the hydrophobicity of the different fractions and their ability to bind dyes such as thioflavin T, Congo red, and 8-anilino-1-naphthalene sulfonate (ANS).