Cross-Seeded Fibrillation Induced by Pyroglutamate-3 and Truncated Aβ40 Variants Leads to Aβ40 Structural Polymorphism Modulation and Elevated Toxicity.

The pathological amyloid plaques in Alzheimer's disease (AD) patients contain not only the wild-type β-amyloid (wt-Aβ) peptide sequences but also a variety of post-translationally modified variants. The pyroglutamate-3 Aβ (pyroE3-Aβ), which is generated from its truncated precursors ΔE3-Aβ, shows the highest abundance among all modified Aβ variants. Previous works have shown that pyroE3-Aβ and/or ΔE3-Aβ, compared with the wild-type sequences, led to a more rapid fibrillation process and final fibrils with higher neuronal cytotoxicity levels. However, much less is known about how the formation of pyroE3/ΔE3-Aβ fibrils would affect the amyloid deposition of wt-Aβ peptides, which are the main pathological events in AD. We show in the present work that the pyroE3/ΔE3-Aβ40 fibrils differ significantly from the wt-Aβ40 fibrils in terms of their molecular structures. When added into monomeric wt-Aβ40 peptides, these variant fibrils can cross-seed the formation of wt-Aβ40 fibrils with fibrillation kinetics that are greater than the self-seeded fibrillation of wt-Aβ40. Furthermore, the cross-seeding process modulates the molecular structures of the yielded wt-Aβ40 fibrils, which show similar features as their variant seeds. The cross-seeded fibrillation process also induces higher cytotoxicity levels compared with the self-seeded fibrillation of wt-Aβ40. Overall, our results support the hypothesis that pyroE3 and ΔE3-Aβ40 variants may serve as triggering factors of the pathological amyloid aggregation of wt-Aβ40 and may underlie the pathological significance of pyroE3/ΔE3-Aβ40 variants on the structural polymorphism of Aβ deposits.