Nerve Growth Factor Gene Delivery across the Blood-Brain Barrier to Reduce Beta Amyloid Accumulation in AD Mice
The therapeutic potential of the nerve growth factor (NGF) gene using brain-targeted liposomal nanoparticles was investigated for the treatment of Alzheimer's disease (AD). We designed brain-targeted gene delivery systems with prolonged systemic circulation and enhanced cellular penetration by conjugating the transferrin (Tf) ligand and the penetratin (Pen) peptide to liposomes via a 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) phospholipid. In vitro characterization studies showed that the nanoparticles had homogeneous particle size and positive zeta potential and were able to protect the plasmid DNA against enzymatic degradation. In vivo brain targeting efficiency of designed liposomes was mimicked using an in vitro triple coculture blood-brain barrier (BBB) model. Liposomal nanoparticles dual-modified with Tf and Pen encasing plasmid NGF efficiently crossed the in vitro BBB model and, subsequently, transfected the primary neuronal cells. Increasing NGF expression in primary neuronal cells following treatment with liposomes increased the levels of the presynaptic marker synaptophysin in vitro. A dose-response study in vivo was performed in order to select the appropriate dose of plasmid NGF to induce significant NGF expression and, consequently, a therapeutic effect. Administration of PenTf-liposomes containing pNGF to amyloid precursor protein (APP)/PS1 mice (aged 3 months) for 4 weeks (one injection per week) significantly decreased (p < 0.05) the levels of toxic soluble and insoluble Aβ peptides as compared to those levels in untreated APP/PS1 mice. Additionally, the treatment stimulated cell proliferation and increased the levels of synaptic markers, synaptophysin and PSD-95. These data suggest the therapeutic potential of PenTf-liposome-mediated NGF gene therapy, and this system can be considered a candidate for the treatment of AD.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
Molecular pharmaceutics - 17(2020), 6 vom: 01. Juni, Seite 2054-2063 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rodrigues, Bruna Dos Santos [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.06.2021 Date Revised 07.06.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.molpharmaceut.0c00218 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM308996178 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The therapeutic potential of the nerve growth factor (NGF) gene using brain-targeted liposomal nanoparticles was investigated for the treatment of Alzheimer's disease (AD). We designed brain-targeted gene delivery systems with prolonged systemic circulation and enhanced cellular penetration by conjugating the transferrin (Tf) ligand and the penetratin (Pen) peptide to liposomes via a 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) phospholipid. In vitro characterization studies showed that the nanoparticles had homogeneous particle size and positive zeta potential and were able to protect the plasmid DNA against enzymatic degradation. In vivo brain targeting efficiency of designed liposomes was mimicked using an in vitro triple coculture blood-brain barrier (BBB) model. Liposomal nanoparticles dual-modified with Tf and Pen encasing plasmid NGF efficiently crossed the in vitro BBB model and, subsequently, transfected the primary neuronal cells. Increasing NGF expression in primary neuronal cells following treatment with liposomes increased the levels of the presynaptic marker synaptophysin in vitro. A dose-response study in vivo was performed in order to select the appropriate dose of plasmid NGF to induce significant NGF expression and, consequently, a therapeutic effect. Administration of PenTf-liposomes containing pNGF to amyloid precursor protein (APP)/PS1 mice (aged 3 months) for 4 weeks (one injection per week) significantly decreased (p < 0.05) the levels of toxic soluble and insoluble Aβ peptides as compared to those levels in untreated APP/PS1 mice. Additionally, the treatment stimulated cell proliferation and increased the levels of synaptic markers, synaptophysin and PSD-95. These data suggest the therapeutic potential of PenTf-liposome-mediated NGF gene therapy, and this system can be considered a candidate for the treatment of AD | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Alzheimer | |
| 650 | 4 | |a NGF | |
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| 700 | 1 | |a Kanekiyo, Takahisa |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Jagdish |e verfasserin |4 aut | |
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