神经营养因子
血脑屏障
脑源性神经营养因子
转染
脂质体
基因传递
药理学
神经保护
中枢神经系统
医学
神经科学
内科学
生物
化学
细胞生物学
受体
生物化学
基因
作者
Sanjay Arora,Divya Sharma,Jagdish Singh
标识
DOI:10.1021/acschemneuro.0c00076
摘要
Alzheimer’s disease (AD), the most common cause of dementia, inflicts enormous suffering to patients and their family members. It is the third deadliest disease, affecting 46.8 million people worldwide. Brain-derived neurotrophic factor (BDNF) is involved in the development, maintenance, and plasticity of the central nervous system. This crucial protein is significantly reduced in AD patients leading to reduced plasticity and neuronal death. In this study, we demonstrate the targeted delivery of the BDNF gene to the brain using liposome nanoparticles. These liposomes were surface modified with glucose transporter-1 targeting ligand (mannose) and cell penetrating peptides (penetratin or rabies virus glycoprotein) to promote selective and enhanced delivery to the brain. Surface modified liposomes showed significantly higher transfection of BDNF in primary astrocytes and neurons, compared to unmodified (plain) liposomes. BDNF transfection via dual modified liposomes resulted in an increase in presynaptic marker synaptophysin protein in primary neuronal cells, which is usually found to be reduced in AD patients. Liposomes surface modified with mannose and cell penetrating peptides demonstrated ∼50% higher transport across the in vitro blood brain barrier (BBB) model and showed significantly higher transfection efficiency in primary neuronal cells compared to plain liposomes. These results were correlated with significantly higher transport of surface modified liposomes (∼7% of injected dose/gram of tissue) and BDNF transfection (∼1.7 times higher than baseline level) across BBB following single intravenous administration in C57BL/6 mice without any signs of inflammation or toxicity. Overall, this study suggests a safe and targeted strategy to increase BDNF protein in the brain, which has the potential to reverse AD pathophysiology.
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