Title : Neuropath: Multi-computational framework for developing a receptor-based transcytosis approach to facilitate BDNF transmission for alzheimer’s progression prevention
Abstract:
Affecting 60-70% of the 55 million dementia patients in the world, Alzheimer's Disease (AD) has established itself as one of the most profound neurodegenerative diseases in today's society. Research has revealed a major reduction in neurochemicals like Brain-Derived Neurotrophic Factor (BDNF) in AD patients, leading to efforts to synthesize and reintroduce it for AD treatment. However, due to BDNF's properties and Blood-Brain-Barrier's (BBB) semi-permeability, there is no accurate and safe BDNF delivery technique today. By targeting the Transferrin Receptor 1 (TFR1) protein on the BBB's surface, a nanoparticle containing BDNF can undergo receptor-mediated transcytosis and enter into the CNS. To develop this, TFR1 and Transferrin were evaluated for their energies using protein-docking algorithms. Clusters with highest energies were then anchored into CHARMM-GUI nanoparticles using glycerophospholipid surface modifications. Prior to drug encapsulation, two novel components were created to increase efficiency of the drug: i) BDNF-TRKB pathway detachable competitive inhibitor to regulate BDNF uptake and prevent external bodily impacts, ii) Novel magnetic nanoparticles with docking mechanisms to apply localized hyperthermia onto amyloid-beta for destructive purposes tested through docking potentials in GROMACs. After encapsulation, alteration of Newton's Law of Viscosity to simplify blood-stream flow was used to apply a force onto the nanoparticle to evaluate stability. Ultimately, the nanoparticle radius of gyration shows a direct effect of the bloodstream on the nanoparticle and described stabilization throughout triangular force application. Results also showcased release of the drug at optimal positions, showcasing efficacy in high-stress artery and CNS environments.
Audience Take Away Notes:
- Utilization of computational modeling tools and technological resources to develop accurate simulations representative of real biological systems
- Direct, targeted drug delivery through the BBB into the CNS space utilizing liposomes with special surface modifications targeting the TFR1 receptor
- Novel framework that can be established for effective, accurate, and rapid development and in-silico testing of targeted drug-delivery
