Peptides with Soft‐Aggregation Behavior Inhibit and Reverse Amyloid‐β Fibrillization

Amyloid-β fibrillization, characterized by ordered and compact peptide assembly, is a hallmark and a key therapeutic target of Alzheimer's disease. However, it is still challenging to completely inhibit or even reverse the fibrillization process. Here, it is reported an anti-fibrillization mechanism mediated by short peptides with a novel soft-aggregation behavior. Unlike classical peptide self-assembly forming ordered nanostructures, several peptides derived from an analgesic peptide underwent dynamic self-aggregation into irregular and loose nanoparticles, which is driven by strong hydrophobic interaction but not by strong hydrogen bonds. By systematically comparing different peptides, it is confirmed a direct correlation between the soft-aggregation behavior and the anti-fibrillization efficacy. It is further demonstrated that Ana-5F, one of these peptides with a superior anti-fibrillization ability, could bind with two core hydrophobic fragments in amyloid-β and effectively inhibit their fibrillization. Consequently, Ana-5F effectively inhibited and reversed fibrillization of full-length amyloid-β. In rat models, Ana-5F cleaned up mature amyloid-β fibrils and protected the animals from cognitive impairment and anxiety-like behaviors. This study, for the first time, defined soft-aggregation as a novel peptide aggregation behavior distinct from classical ordered peptide self-assembly. It also provided a strategic approach to curing Alzheimer's disease by utilizing the soft-aggregation mechanism to eliminate pathological amyloid-β fibrils.