The amyloid hypothesis has been a leading narrative concerning the pathophysiological foundation of Alzheimer’s and Parkinson’s disease. At the two ends of the hypothesis lie the functional protein monomers and the pathology-defining amyloid fibrils, while the early stages of protein aggregation are populated by polymorphic, transient and neurotoxic oligomers. As the structure and activity of oligomers are intertwined, here we show oligomers arising from liquid-liquid phase separation and β-barrel formation, their routes to neurodegeneration, and their role in cerebrovascular perturbation. Together, this Perspective converges on the multifaceted oligomer-axis central to the pathological origin and, hence, the treatment of amyloid diseases.

Amyloid beta spontaneously renders a protein corona on the polystyrene (PS) nanoplastic surface, hindering clearance of the peptide by microglia to amplify neuroimmune dysfunction and Alzheimer's pathology.

The host-defense peptide cathelicidin LL37 inhibits the amyloid aggregation of human islet amyloid polypeptides by hydrophobic associations and pi–pi interactions.

Distinct molecular interactions dictate the diverse aggregations and antimicrobial activities of the host-defense peptide cathelicidin LL37(17–29) and its mutants F17S and I24K.