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

Fibrillogenesis of amyloid β-protein (Aβ) is pathologically associated with Alzheimer's disease (AD), so modulating Aβ 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 Aβ aggregation. However, it is unexpectedly found that the LK7@pID conjugates remarkably promote Aβ fibrillization to form more fibrils than the free Aβ system but effectively eliminate Aβ-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 Aβ molecules and LK7@pID, which triggers Aβ 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 Aβ, and LK7@pID participates in the fibrillization by being embedded in the Aβ fibrils, leading to the formation of hybrid and heterogeneous fibrillar aggregates with a different structure than normal Aβ 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 β-amyloid cytotoxicity.