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

Abstract 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.