Functionalized nanoparticles for brain targeted BDNF gene therapy to rescue Alzheimer's disease pathology in transgenic mouse model.

Brain-derived neurotrophic factor (BDNF) is actively produced and utilized in cortical circuits throughout life to sustain neuronal function and synaptic plasticity. In animal models of Alzheimer's Disease (AD), highly invasive BDNF gene therapy using viral vectors has successfully shown enhanced synaptic protein expression, proliferation of neurons and attenuation of amyloidogenic processes. However, to eliminate virus-related safety issues and invasive procedures, our present study has explored brain-targeted lipid-based nanoparticles that can deliver plasmid encoding BDNF to brain in a safe and efficient manner. Efficacy of these nanoparticles was tested in early (6-months) and advanced stage (9-months) transgenic APP/PS1 AD mice. Liposomes were surface-functionalized with brain targeting ligand, mannose, and cell-penetrating peptides (rabies virus-derived peptide or penetratin). These bifunctionalized nanoparticles enhanced BDNF expression by ~2 times and resulted in >40% (p < 0.05) reduction in toxic amyloid-beta peptides in 6- and 9-months old APP/PS1 mice brains compared to their age-matched untreated controls. Plaque load was reduced ~7 and ~3 times (p < 0.05), respectively, whereas synaptic proteins, synaptophysin and PSD-95, were found to be increased >90% (p < 0.05) in both age groups of transgenic mice treated with bifunctionalized nanoparticles. No untoward adverse effects were observed throughout treatment, suggesting a safe and effective strategy to rescue AD pathology.