Imine-Linked Covalent Organic Framework Modulates Oxidative Stress in Alzheimer's Disease.

ABSTRACT

Oxidative stress due to Cu2+-triggered aggregation of ß-amyloid protein (Aß) and reactive oxygen species (ROS) overexpression in the brain is an important hallmark of early stages of Alzheimer's disease (AD) pathogenesis. The ideal modulator for improving the oxidative stress microenvironment in AD brains should take both Cu2+ and ROS into consideration, which has been rarely reported. Here, a combined therapeutic strategy was achieved by co-encapsulating superoxide dismutase (SOD) and catalase (CAT) in imine-linked covalent organic frameworks (COFs), which were modified with peptide KLVFF (T5). The nanocomposite SC@COF-T5 exhibited an oxidative stress eradicating ability through ROS elimination and Cu2+ chelation, combined with the inhibition of Aß42 monomer aggregation and disaggregation of Aß42 fibrils. In vivo experiments indicated that SC@COF-T5 with a high blood-brain barrier (BBB) penetration efficiency was effective to reduce Aß deposition, expression of pro-inflammatory cytokines, ROS levels, and neurologic damage in AD model mice, consequently rescuing memory deficits of AD mice. This work not only confirms the feasibility and merits of the therapeutic strategy regarding multiple targets for treatment of early AD pathogenesis but also opens up a novel direction for imine-linked COFs in biomedical applications.