TY - JOUR
T1 - Functionalized nanoparticles for brain targeted BDNF gene therapy to rescue Alzheimer's disease pathology in transgenic mouse model
AU - Arora, Sanjay
AU - Kanekiyo, Takahisa
AU - Singh, Jagdish
N1 - Publisher Copyright:
© 2022
PY - 2022/5/31
Y1 - 2022/5/31
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - BDNF
KW - Blood brain barrier
KW - Gene therapy
KW - Liposomes
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U2 - 10.1016/j.ijbiomac.2022.03.203
DO - 10.1016/j.ijbiomac.2022.03.203
M3 - Article
C2 - 35378156
AN - SCOPUS:85128870673
SN - 0141-8130
VL - 208
SP - 901
EP - 911
JO - International Journal of Biological Macromolecules
JF - International Journal of Biological Macromolecules
ER -