Non-invasive Brain Delivery and Efficacy of BDNF in APP/PS1 Transgenic Mice as a Model of Alzheimer's Disease

Abstract

Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) have been demonstrated for their potential as a  neuroregenerative treatment of Alzheimer’s disease (AD).  Unfortunately, most proteins cannot be effectively delivered into the brain from the blood stream due to the presence of the blood-brain barrier (BBB). In this study, we delivered BDNF using ADTC5 as BBB modulator (BBBM) into the brains of a transgenic APP/PS1 mice, a mouse model for AD. As controls, two groups of APP/PS1 mice were treated with BDNF alone and vehicle, respectively. All three groups were subjected to behavioral/cognitive assessments in Y-maze and novel object recognition (NOR) tests as well as evaluation of the brain markers activated by BDNF. The results showed that BDNF + ADTC5 group performed significantly better in both the Y-maze and NOR assessments compared to mice that received BDNF alone or vehicle. In addition, significant upregulations of NG2 receptors as well as EGR1 and ARC mRNA transcripts were observed in the brain cortex of mice treated with BDNF+ADTC5, further indicating the efficacy of delivered BDNF in the brain. In addition, there were significant upregulation of NG2 glia cells as well as EGR1 and ARC mRNA transcripts in the brain cortex compared to controls, indicating the presence of delivered BDNF in the brain. There were high plaque loads in all mice groups, suggesting no influence of BDNF on the plaque formation. In summary, ADTC5 can deliver BDNF into the brains of APP/PS1 mice  and the activity of BDNF in improving cognitive function was likely due to improvement in synaptic plasticity via NG2 glia cells and not by reducing the plaque load.