Brain-targeted RDP-BDNF Fusion Protein Rescues Learning And Memory Ability Of Scopolamine-induced Dementia Mice

Brain-derived neurotrophic factor (BDNF) is a member of neurotrophin family that is generated in the brain and has a widespread distribution in the central nervous system, especially in hippocampus, cortex and striatum. We review data showing that BDNF, in addition to its survival-and growth-promoting actions on a variety of neurons, has powerful synaptic effects--promoting synaptic transmission, synaptic plasticity and synaptic growth. It has been suggested that changes in its level or distribution could be important in the pathogenesis of neurodegenerative conditions in humans and delivery of this therapeutic BDNF protein into brain might produce treatment effects on neurodegenerative diseases. However, how to transport this protein through the blood-brain barrier (BBB), mainly composed of brain capillary endothelial wall and tight junction, is still questionable.If the molecules could cross the blood-brain barrier (BBB) efficiently, they must be equipped with the dual molecular characteristics at least:1) molecular mass under the400-to500-Da threshold;2) high lipid solubility, but BDNF is a large pharmaceutical molecule and cannot cross the BBB efficiently. The invasive procedures involve the usage of the catheter or minipump, and the implantation of biodegradable polyethylene glycol-based hydrogel in which the BDNF is encapsulated. However, this method is not feasible in clinical application for its drawbacks of leading to the secondary complications, limited diffusion and steep concentration gradient. Consequently, significant efforts have been made in recent years to devise new methods and technologies to achieve targeted delivery with high efficiency.Recently, we have showed a novel peptide RDP (a peptide of39amino acid residues:(KSVRTWNEIIPSKGCLRVGGRCHPHVNGGGRRRRRRRRR), derived from the rabies virus glycoprotein (RVG)), is capable of brain-targeting delivery of proteins into neuronal cells, In this study, BDNF was conjugated to the novel cell penetrate peptide RDP and The fusion protein RDP-BDNF was expressed in E. coli BL21(DE3). After the intravenous injection of RDP-BDNF, the time effect curve of RDP-BDNF in the body of mouse was examined. Additionally, Morris water maze test was used to evaluate the effect of RDP-BDNF on scopolamine-induced amnesic mice and the mechanism was also studied. The results of this study indicated that the fusion protein RDP-BDNF exhibited neuroprotective effects on the treatment of cognitive deficit induced by scopolamine in dementia model mice and might provide an avenue to enhance the possibility of BDNF brain-targeted delivery.