Unexpected Function of a Heptapeptide-Conjugated Zwitterionic Polymer that Coassembles into β-Amyloid Fibrils and Eliminates the Amyloid Cytotoxicity

Fibrillogenesis of amyloid beta-protein (A beta) is pathologically associated with Alzheimer's disease (AD), so modulating A beta aggregation is crucial for AD prevention and treatment. Herein, a zwitterionic polymer with short dimethyl side chains (pID) is synthesized and conjugated with a heptapeptide inhibitor (Ac-LVFFARK-NH2, LK7) to construct zwitterionic polymer-inhibitor conjugates for enhanced inhibition of A beta aggregation. However, it is unexpectedly found that the LK7@pID conjugates remarkably promote A beta fibrillization to form more fibrils than the free A beta system but effectively eliminate A beta-induced cytotoxicity. Such an unusual behavior of the LK7@pID conjugates is unraveled by extensive mechanistic studies. First, the hydrophobic environment within the assembled micelles of LK7@pID promotes the hydrophobic interaction between A beta molecules and LK7@pID, which triggers A beta aggregation at the very beginning, making fibrillization occur at an earlier stage. Second, in the aggregation process, the LK7@pID micelles disassemble by the intensive interactions with A beta, and LK7@pID participates in the fibrillization by being embedded in the A beta fibrils, leading to the formation of hybrid and heterogeneous fibrillar aggregates with a different structure than normal A beta fibrils. This unique Trojan horse-like feature of LK7@pID conjugates has not been observed for any other inhibitors reported previously and may shed light on the design of new modulators against beta-amyloid cytotoxicity.

Automated summary

The LK7@pID conjugates unexpectedly promote A beta fibrillization while effectively eliminating A beta-induced cytotoxicity. This unique behavior is unraveled through extensive mechanistic studies, providing insights for the design of new modulators against beta-amyloid cytotoxicity.