Aβ42-Driven α-synuclein Fibril Polymorphism and Distinct Intracellular Aggregation

Aβ42 and α-synuclein aggregates often coexist in neurodegenerative diseases, but the molecular consequences of their interactions remain unclear. This study explored how distinct Aβ42 states—monomers and preformed fibrils (PFFs)—affect α-synuclein fibril formation, structure, and subsequent neuronal damage. Using Thioflavin T kinetics, the researchers found that Aβ42 monomers slowed α-synuclein fibril formation, whereas Aβ42 PFFs promoted accelerated aggregation, suggesting that the aggregation state of Aβ42 influences α-synuclein aggregation.

Further analyses using negative-stain TEM, proteinase K digestion, and solid-state NMR spectroscopy revealed that both Aβ42 monomers and PFFs altered α-synuclein fibril structures, leading to unique fibril conformations depending on Aβ42 concentration and aggregation state. To assess the impact of these structural variations on pathological activity, the team created α-synuclein PFF variants in the presence of varying amounts of Aβ42 monomers or PFFs and tested their effects on dopaminergic neuronal cells.

The α-synuclein fibrils formed alongside Aβ42 PFFs demonstrated a higher potential to trigger intracellular α-synuclein aggregation compared to those formed with Aβ42 monomers. Conversely, fibrils formed with Aβ42 monomers showed seeding capacities similar to or less than those of α-synuclein PFFs.

These findings collectively illustrate that heterotypic interactions between Aβ42 and α-synuclein can reshape α-synuclein aggregation pathways and produce fibril conformations with distinct structural characteristics. Moreover, these variations in fibril structure correlate with differences in neuronal seeding activities. This study provides a molecular basis for understanding how cross-talk between amyloidogenic proteins may contribute to the structural and pathological heterogeneity observed in mixed neurodegenerative diseases.