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. In general, the triggering effects are observed through cross-seeding between the PTM-Aβ seeds and wild-type peptides, which consequently induce modulations in the resultant wild-type fibril structures and elevations in the fibrillar cytotoxicity levels. Modifications with a similar chemical nature, such as the S8-phosphorylation and Y10-nitration, both of which introduce additional side-chain negative charges, show comparable structural-modulation and cytotoxicity-elevation effects. The results imply the biological influences of PTM-Aβ variants on the formation of amyloid deposits through cross-seeded fibrillization.