Polydopamine Modified with Brain Targeting Peptide Rabies Virus Glycoprotein for Treatment of Alzheimer's Disease by Inhibiting Oxidative Stress and Inflammatory Response.

PURPOSE: Polydopamine (PDA) has been recognized as an antioxidant and anti-inflammatory agent. However, the difficulty to cross blood-brain barrier (BBB) limits PDA's neuroprotective effects in the brain. Here, we aimed to construct PDA-rabies virus glycoprotein (RVG) by modifying the RVG29 polypeptide on PDA nanoparticles (NPs) and investigate whether PDA-RVG improved the cognitive function and pathology of Alzheimer's Disease (AD) by inhibiting oxidative stress and inflammatory response.

METHODS

We prepared and characterized PDA NPs and tested whether PDA improved AD pathology in APP/PS1 mice. To facilitate PDA's penetration across BBB, we modified RVG29 on PDA and examined its brain-specific targeting ability and biocompatibility. We further tested the effects of PDA-RVG on oxidative stress, inflammatory response and ferroptosis in both in vitro and in vivo AD models.

RESULTS

PDA demonstrated robust reactive oxygen species (ROS)-scavenging activity and effectively reduced Aβ deposition and the expression of APP and PS1 in APP/PS1 mice. PDA-RVG successfully crossed BBB in an in vitro BBB model. Meanwhile, compared with PDA, PDA-RVG intravenous injection exhibited good brain-specific targeting ability. Moreover, the hematological analysis revealed no significant differences between the PDA-RVG and control groups. In the in vitro AD experiment, PDA-RVG reduced ROS, inducible nitric oxide synthase, and pro-inflammatory cytokines levels in BV2 cells. Besides, PDA-RVG decreased ROS and apoptosis, while increased glutathione peroxidase4 (GPX4) and the viability of PC12 cells. More importantly, intravenous delivery of PDA-RVG improved cognitive function assessed by Morris water maze, and upregulated the ferroptosis-protective proteins Ferritin Heavy Chain 1 and GPX4 expression, while PDA alone did not lead to cognitive improvement.

CONCLUSION

PDA reduces AD pathology, which is possibly attributed to its ability to scavenge ROS, ameliorate the inflammatory microenvironment and inhibit ferroptosis. Intravenous delivery of PDA-RVG has good brain-specific targeting ability and biocompatibility, and improves cognitive function in AD mice. This study provides a safe, effective, and promising therapeutic strategy for AD via oxidative stress-associated target.