Schlenzig D, Rönicke R, Cynis H, Ludwig HH, Scheel E, Reymann K, Saido T, Hause G, Schilling S, Demuth HU.
N-Terminal pyroglutamate formation of Aβ38 and Aβ40 enforces oligomer formation and potency to disrupt hippocampal long-term potentiation.
J Neurochem. 2012 Jun;121(5):774-84.
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Nussbaum et al. show that when as little as 5 percent of Aβ is in the pyroglutamylated N-truncated form (Aβ 3(pE)-42), it confers toxicity to a solution of Aβ1-42 monomers. The authors suggest that Aβ42 undergoes prion-like templated conversion induced by the 3(pE)-42 seed. Given that Aβ aggregation is a self-propagating phenomenon, even a minute amount of seed may be sufficient to drive amplification of toxic Aβ aggregates.
It is also interesting that the authors carefully control time, buffer, and concentrations, as all these factors influence the final equilibrium between toxic and non-toxic species in the Aβ mixture. The principle that small alterations in Aβ species have strong effects on the final biological and toxic effects of Aβ is, however, not novel (see, e.g., Kuperstein et al., 2010, and Pauwels et al., 2011). As a note of caution, it is not very clear why the authors did not find any pathogenic effects of Aβ42 at low micromolar concentration, and what would happen if they used more abundant Aβ40 instead of Aβ42 as a substrate for seeding. The authors also do not comment on other amyloid fragments that may serve as templates and induce toxic conformations (Aβ43, Saito et al., 2011; phosphorylated Aβ, Kumar et al., 2011; different kind of oligomers, and so on).
Intriguingly, the authors show that the hybrid pE-Aβ oligomers may exist in vivo (though patient number was quite limited), but do not proceed with further characterization of these species. Nevertheless, it is an interesting work that potentially provides new insights into amyloid toxicity in AD.
Kuperstein I, Broersen K, Benilova I, Rozenski J, Jonckheere W, Debulpaep M, Vandersteen A, Segers-Nolten I, Van Der Werf K, Subramaniam V, Braeken D, Callewaert G, Bartic C, D'Hooge R, Martins IC, Rousseau F, Schymkowitz J, De Strooper B.
Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio.
EMBO J. 2010 Oct 6;29(19):3408-20.
Pauwels K, Williams TL, Morris KL, Jonckheere W, Vandersteen A, Kelly G, Schymkowitz J, Rousseau F, Pastore A, Serpell LC, Broersen K.
Structural basis for increased toxicity of pathological aβ42:aβ40 ratios in Alzheimer disease.
J Biol Chem. 2012 Feb 17;287(8):5650-60.
Saito T, Suemoto T, Brouwers N, Sleegers K, Funamoto S, Mihira N, Matsuba Y, Yamada K, Nilsson P, Takano J, Nishimura M, Iwata N, Van Broeckhoven C, Ihara Y, Saido TC.
Potent amyloidogenicity and pathogenicity of Aβ43.
Nat Neurosci. 2011 Aug;14(8):1023-32.
Kumar S, Rezaei-Ghaleh N, Terwel D, Thal DR, Richard M, Hoch M, Mc Donald JM, Wüllner U, Glebov K, Heneka MT, Walsh DM, Zweckstetter M, Walter J.
Extracellular phosphorylation of the amyloid β-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease.
EMBO J. 2011 Jun 1;30(11):2255-65.
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