Heptameric Peptide Interferes with Amyloid-β Aggregation by Structural Reorganization of the Toxic Oligomers.

Pathogenesis of Alzheimer's disease (AD), the most common type of dementia, involves misfolding and aggregation of the extracellular amyloid-β (Aβ) protein where the intermediate oligomers, formed during the aggregation progression cascade, are considered the prime toxic species. Here, we identify an active peptide fragment from a medicinal plant-derived () fibrinolytic enzyme having anti-amyloidogenic effects against Aβ fibrillation and toxicity. Liquid chromatography with tandem mass spectrometry (LC-MS/MS), followed by computational analysis of the peptide pool generated by proteolytic digestion of the enzyme, identifies two peptide sequences with predictive high-propensity binding to Aβ. Microscopic visualizations in conjunction with biochemical and biophysical assessments suggest that the synthetic version of one of the peptides (termed here P, GFLLHQK) arrests Aβ molecules in off-pathway oligomers that can no longer participate in the cytotoxic fibrillation pathway. In contrast, the other peptide (termed P) aggravates the fibrillation process. Further investigations confirm the strong binding affinity of P with both Aβ monomers and toxic oligomers by biolayer interferometric assays. We have also shown that, mechanistically, P binding induces conformational alterations in the Aβ molecule along with modification of Aβ hydrophobicity, one of the key players in aggregation. Importantly, the biostability of P in human blood serum and its nontoxic nature make it a promising therapeutic candidate against Alzheimer's, for which no disease-modifying treatments are available to date.