Modulation of aggregation and structural polymorphisms of β-amyloid fibrils in cellular environments by pyroglutamate-3 variant cross-seeding.

Amyloidogenic deposition of β-amyloid (Aβ) peptides in human brain involves not only the wild-type Aβ (wt-Aβ) sequences, but also posttranslationally modified Aβ (PTM-Aβ) variants. Recent studies hypothesizes that the PTM-Aβ variants may trigger the deposition of wt-Aβ, which underlies the pathology of Sporadic Alzheimer's disease. Among PTM-Aβ variants, the pyroglutamate-3-Aβ (E3-Aβ) has attracted much attention because of their significant abundances and broad distributions in senile plaques and dispersible and soluble oligomers.

Cross-Seeded Fibrillation Induced by Pyroglutamate-3 and Truncated Aβ Variants Leads to Aβ 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.

N-Terminal Modified Aβ Variants Enable Modulations to the Structures and Cytotoxicity Levels of Wild-Type Aβ Fibrils through Cross-Seeding.

Post-translational modifications (PTMs) of β-amyloid (Aβ) peptides are considered as triggering factors in sporadic Alzheimer's disease. However, studies to show the influence of pre-existing PTM-Aβ fibrils on wild-type Aβ peptides, which directly mimic the triggering scenarios, are rare. Here we show that three types of pathologically relevant PTM-Aβ variants with modifications in a particular segment (from D7 to V12) of the primary sequence lead to distinct impacts on the fibrillization of wild-type Aβ peptides.