Anti-aggregant tau mutant promotes neurogenesis.
Anti-aggregant tau mutant promotes neurogenesis.
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DOI：
10.1186/s13024-017-0230-8
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发表时间：
2017-12-04
影响因子：
15.1
通讯作者：
Mandelkow EM
中科院分区：
文献类型：
--
作者：
Joseph M;Anglada-Huguet M;Paesler K;Mandelkow E;Mandelkow EM
微管相关蛋白Tau在神经退行性变和神经再生中发挥作用。先前的工作表明，前聚集型突变体Tau重复结构域的表达会导致海马区的强烈聚集和明显的神经元丢失，而反聚集型没有任何有害影响。这两种蛋白质的主要不同之处在于它们形成ç结构的倾向，从而聚集在一起。为了阐明这些对比效应的基础，我们分析了来自表达Tau重复结构域(RD)和反聚集突变(TauRDΔKPP)的转基因小鼠的器官型海马片培养(OHSC)，并将它们与含有前聚集TauRDΔK的切片进行比较。通过敏感的生物发光报告基因分析(荧光素酶)监测海马区转基因表达。由于神经发生的增强，抗聚集物TauRDΔKPP的表达导致年轻时海马区体积更大，导致神经元数量增加。没有小胶质细胞和星形胶质细胞激活的迹象，表明没有炎症反应。对信号转导通路的研究表明，WNT-5a的表达明显减少，而WNT3的表达明显增加。早在P8就观察到海马干细胞增殖的显著增加(BrdU所见)，尤其是在通常不观察到神经发生的CA区域。神经元的增加一直持续到16个月龄。这些数据表明，抗聚集物TauRDWntkpp的表达促进了典型的Δ信号通路介导的海马神经发生，而不是炎症反应。这项研究指出了tau在大脑发育和神经发生中的作用，而不是它在晚年神经退化中的有害作用。本文的在线版本(10.1186/s130240170230-8)包含补充材料，授权用户可以使用。
The microtubule-associated protein Tau plays a role in neurodegeneration as well as neurogenesis. Previous work has shown that the expression of the pro-aggregant mutant Tau repeat domain causes strong aggregation and pronounced neuronal loss in the hippocampus whereas the anti-aggregant form has no deleterious effects. These two proteins differ mainly in their propensity to form ß structure and hence to aggregate. To elucidate the basis of these contrasting effects, we analyzed organotypic hippocampal slice cultures (OHSCs) from transgenic mice expressing the repeat domain (RD) of Tau with the anti-aggregant mutation (TauRDΔKPP) and compared them with slices containing pro-aggregant TauRDΔK. Transgene expression in the hippocampus was monitored via a sensitive bioluminescence reporter gene assay (luciferase). The expression of the anti-aggregant TauRDΔKPP leads to a larger volume of the hippocampus at a young age due to enhanced neurogenesis, resulting in an increase in neuronal number. There were no signs of activation of microglia and astrocytes, indicating the absence of an inflammatory reaction. Investigation of signaling pathways showed that Wnt-5a was strongly decreased whereas Wnt3 was increased. A pronounced increase in hippocampal stem cell proliferation (seen by BrdU) was observed as early as P8, in the CA regions where neurogenesis is normally not observed. The increase in neurons persisted up to 16 months of age. The data suggest that the expression of anti-aggregant TauRDΔKPP enhances hippocampal neurogenesis mediated by the canonical Wnt signaling pathway, without an inflammatory reaction. This study points to a role of tau in brain development and neurogenesis, in contrast to its detrimental role in neurodegeneration at later age. The online version of this article (10.1186/s13024-017-0230-8) contains supplementary material, which is available to authorized users.
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影响因子：
4.3
作者：
Gebara E;Sultan S;Kocher-Braissant J;Toni N
通讯作者：
Toni N
影响因子：
34.7
作者：
Clarke, Laura E.;Barres, Ben A.
通讯作者：
Barres, Ben A.
DOI：
10.1523/jneurosci.3252-09.2009
发表时间：
2009-12-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Fjell AM;Walhovd KB;Fennema-Notestine C;McEvoy LK;Hagler DJ;Holland D;Brewer JB;Dale AM
通讯作者：
Dale AM
影响因子：
4.2
作者：
Anderson, KJ;Fugaccia, I;Scheff, SW
通讯作者：
Scheff, SW
影响因子：
2.5
作者：
Dayer, AG;Ford, AA;Cameron, HA
通讯作者：
Cameron, HA