Nature, published online 2 May 2012, doi:10.1038/nature11060

Credit: JUSTIN NUSSBAUM

Toxic oligomeric forms of amyloid β (Aβ) peptides, including Aβ1–42 and the N-terminally truncated pyroglutamated (pE) Aβ3(pE)–42 peptides, are linked to Alzheimer's disease (AD) pathology. Nussbaum et al. now uncover a molecular mechanism by which Aβ3(pE)–42 peptides exert their cytotoxic effects. The authors observed that the Aβ3(pE)–42 peptides or a mix of Aβ3(pE)–42 and excess Aβ1–42 peptides oligomerized more slowly than Aβ1–42 alone and were more toxic and metastable. Fractionation of the Aβ3(pE)–42–Aβ1–42 hybrid oligomers and cytotoxicity assays showed that the toxic species were low-molecular-weight oligomers. They observed that serial dilutions of Aβ3(pE)–42–Aβ1–42 oligomers with monomeric Aβ1–42 led to the formation of toxic Aβ1–42 oligomers without further addition of Aβ3(pE)–42, suggesting that Aβ3(pE)–42 indeed has prion-like activity; it induces misfolding and aggregation of other peptides. Importantly, Aβ3(pE)–42 oligomers were detected in brain lysates of patients with AD, and transgenic mice with increased amounts of Aβ3(pE)–42 showed AD-like pathology. In agreement with the observations that Aβ3(pE)–42 peptide has prion-like activity, injection of hybrid Aβ3(pE)–42–Aβ1–42 oligomers into the brains of mice with AD led to faster accumulation of Aβ plaques. This study provides evidence that the pE-Aβ peptides can prime the formation of toxic Aβ oligomers and function as prion-like species.