FGF-2 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington's disease
FGF-2 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington's disease
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DOI：
10.1073/pnas.0506375102
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发表时间：
2005-12-13
影响因子：
11.1
通讯作者：
Ellerby, LM
中科院分区：
文献类型：
--
作者：
Jin, KL;LaFevre-Bernt, M;Ellerby, LM
对于亨廷顿氏病（HD）没有令人满意的治疗，亨廷顿氏病是一种遗传性神经退行性疾病，可引起舞蹈病、痴呆和死亡。一种潜在的治疗策略涉及通过刺激内源性神经元前体的增殖（神经发生）及其迁移到脑的受损区域来替换死亡的神经元。由于生长因子在某些情况下具有神经保护作用，并且还可以刺激神经发生，因此我们从8周龄开始通过皮下注射HD转基因R6/2小鼠直至死亡。给予FGF-2。FGF-2使野生型小鼠脑室下区的增殖细胞数量增加约30%，在HD转基因R6/2小鼠中增加约150%。FGF-2还诱导新神经元从室管膜下区募集到HD转基因R6/2小鼠的新纹状体和大脑皮质中。在纹状体中，这些神经元是DARPP-32表达的中等多刺神经元，与HD中丢失的神经元的表型一致。FGF-2也是神经保护性的，因为它阻断了原代纹状体培养物中突变扩增的Htt诱导的细胞死亡。FGF-2还减少聚谷氨酰胺聚集体，改善运动性能，并延长寿命约20%。我们的结论是，FGF-2改善神经功能缺损和长寿的转基因小鼠模型的HD，其神经保护和神经增殖作用可能有助于这种改善。
There is no satisfactory treatment for Huntington's disease (HD), a hereditary neurodegenerative disorder that produces chorea, dementia, and death. One potential treatment strategy involves the replacement of dead neurons by stimulating the proliferation of endogenous neuronal precursors (neurogenesis) and their migration into damaged regions of the brain. Because growth factors are neuroprotective in some settings and can also stimulate neurogenesis, we treated HD transgenic R6/2 mice from 8 weeks of age until death by s.c. administration of FGF-2. FGF-2 increased the number of proliferating cells in the subventricular zone by approximate to 30% in wild-type mice, and by approximate to 150% in HD transgenic R6/2 mice. FGF-2 also induced the recruitment of new neurons from the subventricular zone into the neostriatum and cerebral cortex of HD transgenic R6/2 mice. In the striatum, these neurons were DARPP-32-expressing medium spiny neurons, consistent with the phenotype of neurons lost in HD. FGF-2 was neuroprotective as well, because it blocked cell death induced by mutant expanded Htt in primary striatal cultures. FGF-2 also reduced polyglutamine aggregates, improved motor performance, and extended lifespan by approximate to 20%. We conclude that FGF-2 improves neurological deficits and longevity in a transgenic mouse model of HD, and that its neuroprotective and neuroproliferative effects may contribute to this improvement.