Beyond Co-Existence: α-Synuclein Sequesters Amyloid-β42 into Distinct Hybrid Assemblies

Neurodegenerative comorbidity is common, with amyloid-{beta} (A{beta}) deposits often appearing in Parkinsons disease and Lewy-body (-synuclein, -syn) pathology in Alzheimers disease. However, the early stage mechanism remains unclear. Does -syn suppress A{beta}42 nucleation, scaffold it, or shift which aggregates persist long enough to be pathogenic? We used all-atom explicit-solvent molecular dynamics to compare three scenarios: (i) -syn with an A{beta}42 monomer, (ii) -syn with two A{beta}42 monomers, and (iii) -syn with an A{beta}42 monomer and a preformed A{beta}42 dimer. Each system was simulated in five independent replicates of 3 {micro}s (45 {micro}s total), and we quantified aggregation events, contact interfaces, and {beta}-hairpin motifs in A{beta}42. Across all systems, -syn contacted A{beta}42 repeatedly, but the dominant binding surfaces shifted with the oligomeric state of A{beta}42. With monomeric A{beta}42, -syn fre-quently engaged the A{beta}42 central hydrophobic core and C-terminus through its N-terminal and NAC regions. In the most persistent heterodimers, sustained {beta}-hairpin formation in A{beta}42 was rare, consistent with a shielding mode that limits intramolecular C-terminus[->]CHC interactions linked to hairpin nucleation. When a stable A{beta}42 dimer was present, -syn bound mainly to exposed termini and did not invade the dimers {beta}-sheet core; the dimer retained continuous hairpin signatures. In one trajectory, -syn tethered the monomer C-terminus while leaving the CHC accessible, coinciding with a long-lived {beta}-hairpin in the monomer. Together, these trajectories support a context-dependent picture: -syn can sup-press the conformational maturation of monomeric A{beta}42, yet also associate with and potentially stabilize structured A{beta}42 oligomers through peripheral binding.