Allopregnanolone Promotes Neuronal and Oligodendrocyte DifferentiationIn VitroandIn Vivo: Therapeutic Implication for Alzheimer's Disease
Allopregnanolone Promotes Neuronal and Oligodendrocyte DifferentiationIn VitroandIn Vivo: Therapeutic Implication for Alzheimer's Disease
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DOI：
10.1007/s13311-020-00874-x
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发表时间：
2020-07-06
影响因子：
5.7
通讯作者：
Brinton, Roberta Diaz
中科院分区：
文献类型：
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作者：
Chen, Shuhua;Wang, Tian;Brinton, Roberta Diaz
先前的研究表明，内源性神经甾体别孕烯醇酮（Allo）在体外和体内促进啮齿动物和人神经祖细胞/神经干细胞（NSC）的再生，并恢复阿尔茨海默病（3xTgAD）的雄性三重转基因小鼠模型（3xTgAD）的神经发生和认知功能。在这项研究中，我们研究了同种异体调节成年小鼠神经干细胞的神经元分化的性别。结果表明，与年龄匹配的非Tg神经干细胞相比，3xTgAD成人神经干细胞中神经元向神经胶质细胞分化的年龄依赖性转变加速并放大。与神经元分化的下降相一致，3xTgAD小鼠中未成熟神经元的数量较早下降，这与老年阿尔茨海默氏症人脑中的观察结果一致。Allo处理恢复了源自成人3xTgAD NSC的神经元/星形胶质细胞比率，并增加了3xTgAD脑中的NSC增殖和分化。Allo治疗还显著增加了3xTgAD小鼠胼胝体中寡突胶质细胞前体细胞标志物Olig 2以及Olig 2阳性细胞的表达。胰岛素样生长因子-1（IGF-1）和IGF-1受体（IGF-1 R）的表达水平增加，可促进神经元和少突胶质细胞分化。总的来说，这些发现与Allo作为一种多效性治疗剂促进阿尔茨海默氏症大脑中灰质和白色物质的再生是一致的。
Previous studies demonstrated that the endogenous neurosteroid allopregnanolone (Allo) promotes regeneration of rodent and human neural progenitor/neural stem cells (NSCs)in vitroandin vivo, and restores neurogenesis and cognitive function in the male triple transgenic mouse model of Alzheimer's disease (3xTgAD). In this study, we investigated Allo regulation of neuronal differentiation of adult mouse neural stem cells from both sexes. Outcomes indicated that the age-dependent shift from neuronal to glial differentiation was accelerated and magnified in 3xTgAD adult NSCs compared to that in age-matched non-Tg NSCs. Coincident with the decline in neuronal differentiation, the number of immature neurons declined earlier in 3xTgAD mice, which was consistent with observations in the aged Alzheimer's human brain. Allo treatment restored the neuron/astrocyte ratio derived from adult 3xTgAD NSCs and increased both NSC proliferation and differentiation in the 3xTgAD brain. Allo treatment also significantly increased expression of Olig2, an oligodendrocyte precursor cell marker, as well as Olig2-positive cells in the corpus callosum of 3xTgAD mice. Increased neuronal and oligodendrocyte differentiation was paralleled by an increase in the expression levels of insulin-like growth factor-1 (IGF-1) and IGF-1 receptor (IGF-1R). Collectively, these findings are consistent with Allo acting as a pleiotropic therapeutic to promote regeneration of gray and white matter in the Alzheimer's brain.