Amyloid plaques comprising misfolded proteins are the hallmark of several incurable diseases, including Alzheimer's disease, type-II diabetes, Jacob-Creutzfeld disease, and others. While the exact molecular mechanisms underlying protein misfolding diseases are still unknown, several theories account for amyloid fiber formation and their toxic significance. Prominent among those is the "prion hypothesis" stipulating that misfolded protein seeds act as "infectious agents" propagating aggregation of nominally healthy, native proteins. Recent studies, in fact, have reported that interactions between different amyloid peptides that are partly sequence-related might also affect fibrillation pathways and pathogenicity. Here, we present evidence that two structurally and physiologically unrelated amyloidogenic peptides, the islet amyloid polypeptide (IAPP, the peptide comprising the amyloid aggregates in type II diabetes) and an amyloidogenic determinant of the prion protein (PrP), give rise to a significantly distinct fibrillation pathway when they are incubated together in the presence of membrane bilayers. In particular, the experimental data demonstrate that the lipid bilayer environment is instrumental in initiating and promoting the assembly of morphologically distinct fibrillar species. Moreover, cross-fibrillation produced peptide species exhibiting significantly altered membrane interaction profiles, as compared to the scenario where the two peptides aggregated separately. Overall, our data demonstrate that membranes constitute a critical surface-active medium for promoting interactions between disparate amyloidogenic peptides, modulating both fibrillation pathways as well as the biophysical properties of the peptide aggregates. This work hints that membrane-induced cross-fibrillation of unrelated amyloidogenic peptides might play an insidious role in the molecular pathologies of protein misfolding diseases.
ASJC Scopus subject areas
- General Chemistry
- Colloid and Surface Chemistry