Compelling evidence implicates self-assembly of amyloid-β (Aβ 1-42) peptides into soluble oligomers and fibrils as a major underlying event in Alzheimer's disease (AD) pathogenesis. Herein, we employed amyloid-degrading keratinase (kerA) enzyme as a key Aβ 1-42-binding scaffold to identify five keratinase-guided peptides (KgPs) capable of interacting with and altering amyloidogenic conversion of Aβ 1-42 The KgPs showed micromolar affinities with Aβ 1-42 and abolished its sigmoidal amyloidogenic transition, resulting in abrogation of fibrillogenesis. Comprehensive assessment using dynamic light scattering (DLS), atomic force microscopy (AFM) and Fourier-transform infrared (FTIR) spectroscopy showed that KgP... More
Compelling evidence implicates self-assembly of amyloid-β (Aβ 1-42) peptides into soluble oligomers and fibrils as a major underlying event in Alzheimer's disease (AD) pathogenesis. Herein, we employed amyloid-degrading keratinase (kerA) enzyme as a key Aβ 1-42-binding scaffold to identify five keratinase-guided peptides (KgPs) capable of interacting with and altering amyloidogenic conversion of Aβ 1-42 The KgPs showed micromolar affinities with Aβ 1-42 and abolished its sigmoidal amyloidogenic transition, resulting in abrogation of fibrillogenesis. Comprehensive assessment using dynamic light scattering (DLS), atomic force microscopy (AFM) and Fourier-transform infrared (FTIR) spectroscopy showed that KgPs induced the formation of off-pathway oligomers comparatively larger than the native Aβ 1-42 oligomers but with a significantly reduced cross-β signature. These off-pathway oligomers exhibited low immunoreactivity against oligomer-specific (A11) and fibril-specific (OC) antibodies and rescued neuronal cells from Aβ 1-42 oligomer toxicity as well as neuronal apoptosis. Structural analysis using molecular docking and molecular dynamics (MD) simulations showed two preferred KgP binding sites (Lys16-Phe20 and Leu28-Val39) on the NMR ensembles of monomeric and fibrillar Aβ 1-42, indicating an interruption of crucial hydrophobic and aromatic interactions. Overall, our results demonstrate a new approach for designing potential anti-amyloid molecules that could pave way for developing effective therapeutics against AD and other amyloid diseases.,© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
