A Hydroxyquinoline Polymer with Excellent Amyloidosis Inhibition and Protein Delivery Ability to Combat Amyloid-β-Mediated Neurotoxicity.

Abstract

The accumulation of abnormal protein deposits known as amyloid-β (Aβ) plaques contributes to the development and progression of Alzheimer's disease. Aggregated Aβ exacerbates oxidative stress by stimulating the production of reactive oxygen species (ROS) in a detrimental feedback loop. 8-Hydroxyquinoline (8-HQ) is recognized for its ability to inhibit or reverse Aβ aggregation and reduce neurotoxicity. Here, an 8-HQ-based polymer, DHQ, was developed to combat Aβ-mediated neurotoxicity by delivering an antioxidant enzyme. DHQ efficiently delivers superoxide dismutase into targeted cells, thereby downregulating the intracellular ROS level. Additionally, the polymer effectively inhibits the fibrillization of three proteins involved in fibrosis, β-lactoglobulin (BLG), insulin, and Aβ1-40, at nanomolar concentrations. Cell culture models demonstrated that DHQ reduces ROS levels induced by Aβ1-40 aggregation, rescuing cell viability and preventing apoptosis. Intracellular delivery of SOD further enhanced the ability to maintain the ROS homeostasis. This polymer offers a multifaceted approach to treating diseases associated with amyloidosis.