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Mirbaha H, Holmes BB, Sanders DW, Bieschke J, Diamond MI. Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation. J Biol Chem. 2015 Jun 12;290(24):14893-903. Epub 2015 Apr 17 PubMed.
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Konkuk University
The work by Mirbaha et al. provides strong evidence that tau trimer is the minimal unit that is required for both entry to cells and induction of tau aggregation inside cells, hence for cell-to-cell transmission of the aggregates. The authors elegantly characterized the oligomers with various sizes that are derived from in vitro-generated repeat domain fibrils and brain-derived aggregates prepared from the brain tissues of Alzheimer patients, and both preparations exhibited essentially the same results. This is the most advanced work so far in terms of characterization of size-species with propagation ability and makes a strong case for the trimer being the smallest unit for uptake and aggregate induction.
I would like to point out a few things that might be important in interpreting this interesting work. First, it relies on the premise that the fibril breakdown products are identical to de novo oligomers that are en route to fibrils. The forward/assembly process may involve a different set of oligomeric intermediates from the reverse/disassembly process. Second, when comparing the activities of oligomers and higher-order aggregates, one has to take into consideration the difference between activity per-mole of monomer equivalents and activity per-particle. The current work shows that the trimers are not more efficient in “seeding” aggregation on the monomer mole basis. That indicates relatively low per-particle activity. Finally, one cannot rule out the possibility that the trimers have to convert to larger assemblies before being able to “seed” aggregation in cells. In any case, thanks to this work, we might have the minimum unit of tau assembly that contains all the information required for cell-to-cell propagation of tau pathology.
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