Bone marrow-derived microglia-based neurturin delivery protects against dopaminergic neurodegeneration in a mouse model of Parkinson's disease.
Bone marrow-derived microglia-based neurturin delivery protects against dopaminergic neurodegeneration in a mouse model of Parkinson's disease.
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DOI：
10.1016/j.neulet.2012.12.034
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发表时间：
2013-02-22
影响因子：
2.5
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Biju KC;Santacruz RA;Chen C;Zhou Q;Yao J;Rohrabaugh SL;Clark RA;Roberts JL;Phillips KA;Imam SZ;Li S
尽管神经营养因子长期以来一直被认为是防止神经元退行性变的有效药物，但治疗帕金森病和其他神经退行性疾病的临床成功一直受到营养因子通过血脑屏障（BBB）输送困难的阻碍。骨髓造血干细胞为基础的基因治疗正在成为克服药物递送问题的一种有前途的工具，因为骨髓细胞可以穿过血脑屏障，并被大量招募到神经退行性疾病的部位，在那里它们成为激活的小胶质细胞，可以分泌营养因子。我们测试了骨髓源性小胶质传递神经蛋白（NTN）保护小鼠多巴胺能神经元免受神经毒素诱导的死亡的功效。用慢病毒在体外转染骨髓细胞，慢病毒在合成巨噬细胞特异性启动子的驱动下表达NTN基因。然后收集受感染的骨髓细胞并移植到受体动物体内。移植后8周，给小鼠注射神经毒素1-甲基-4-苯基-1,2,3,6-四氢嘌呤（MPTP） 7天，诱导多巴胺能性神经变性。小胶质细胞介导的NTN递送可显著改善mptp诱导的纹状体黑质酪氨酸羟化酶（TH）阳性神经元的变性。小胶质细胞介导的NTN递送也诱导mptp处理动物纹状体突触标记物染色显著恢复。功能上，NTN处理恢复了mptp引起的一般活动、饲养行为和食物摄入量的下降。因此，骨髓源性小胶质细胞可以作为持续递送神经营养因子的细胞载体，能够减轻多巴胺能损伤。
Although neurotrophic factors have long been recognized as potent agents for protecting against neuronal degeneration, clinical success in treating Parkinson’s disease and other neurodegenerative disorders has been hindered by difficulties in delivery of trophic factors across the blood brain barrier (BBB). Bone marrow hematopoietic stem cell-based gene therapy is emerging as a promising tool for overcoming drug delivery problems, as myeloid cells can cross the BBB and are recruited in large numbers to sites of neurodegeneration, where they become activated microglia that can secrete trophic factors. We tested the efficacy of bone marrow-derived microglial delivery of neurturin (NTN) in protecting dopaminergic neurons against neurotoxin-induced death in mice. Bone marrow cells were transduced ex vivo with lentivirus expressing the NTN gene driven by a synthetic macrophage-specific promoter. Infected bone marrow cells were then collected and transplanted into recipient animals. Eight weeks after transplantation, the mice were injected with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropuridine (MPTP) for seven days to induce dopaminergic neurodegeneration. Microglia-mediated NTN delivery dramatically ameliorated MPTP-induced degeneration of tyrosine hydroxylase (TH)-positive neurons of the substantia nigra and their terminals in the striatum. Microglia-mediated NTN delivery also induced significant recovery of synaptic marker staining in the striatum of MPTP-treated animals. Functionally, NTN treatment restored MPTP-induced decline in general activity, rearing behavior, and food intake. Thus, bone marrow-derived microglia can serve as cellular vehicles for sustained delivery of neurotrophic factors capable of mitigating dopaminergic injury.
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影响因子：
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作者：
Ramaswamy, Shilpa;Soderstrom, Katherine E.;Kordower, Jeffrey H.
通讯作者：
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影响因子：
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作者：
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通讯作者：
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