Human tau expression reduces adult neurogenesis in a mouse model of tauopathy.
Human tau expression reduces adult neurogenesis in a mouse model of tauopathy.
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DOI：
10.1016/j.neurobiolaging.2015.03.002
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发表时间：
2015-06
影响因子：
4.2
通讯作者：
Lamb BT
中科院分区：
文献类型：
--
作者：
Komuro Y;Xu G;Bhaskar K;Lamb BT
过度磷酸化和聚集的微管相关蛋白tau （MAPT）的积累是一类被称为tau病的神经退行性疾病的中心特征。值得注意的是，越来越多的证据表明，包括阿尔茨海默病在内的牛头病变也以神经发生（成年神经元的诞生）减少为特征。然而，过度磷酸化和MAPT聚集与神经源性缺陷之间的确切关系尚不清楚，包括这是早期还是晚期疾病标志物。在目前的研究中，我们利用基于基因组的小鼠tau模型来研究疾病过程中成人神经发生的时间和空间调节。令人惊讶的是，早在2个月大时，hTau小鼠在两个不同的大脑区域显示出成年神经发生的减少，这是在该模型中强大的MAPT病理发展之前。这种减少被发现是由于海马的增殖减少而不是细胞凋亡增加。在这些时间点，hTau小鼠也表现出神经源性前体MAPT磷酸化的改变。为了研究MAPT对神经发生的影响是否具有细胞自主性，我们在体外检测了从hTau动物制备的神经球，发现与非转基因神经球培养物相比，MAPT对神经发生的影响存在生长缺陷。综上所述，这些研究提供的证据表明，成人神经发生改变是hTau小鼠牛头病模式中MAPT细胞自主功能改变的一个强大的早期标记，并且成人神经发生改变应该作为人类牛头病的潜在标记和治疗靶点进行研究。
Accumulation of hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) is a central feature of a class of neurodegenerative diseases termed tauopathies. Notably, there is increasing evidence that tauopathies, including Alzheimer's disease, are also characterized by a reduction in neurogenesis, the birth of adult neurons. However, the exact relationship between hyperphosphorylation and aggregation of MAPT and neurogenic deficits remains unclear, including whether this is an early- or late-stage disease marker. In the current study, we utilized the genomic –based hTau mouse model of tauopathy to examine the temporal and spatial regulation of adult neurogenesis during the course of disease. Surprisingly, hTau mice exhibited reductions in adult neurogenesis in two different brain regions by as early as 2 months of age, prior to the development of robust MAPT pathology in this model. This reduction was found to be due to reduced proliferation and not enhanced apoptosis in the hippocampus. At these same time points, hTau mice also exhibited altered MAPT phosphorylation with neurogenic precursors. To examine whether the effects of MAPT on neurogenesis were cell autonomous, neurospheres prepared from hTau animals were examined in vitro, revealing a growth deficit when compared to nontransgenic neurosphere cultures. Taken together, these studies provide evidence that altered adult neurogenesis is a robust and early marker of altered, cell-autonomous function of MAPT in the hTau mouse mode of tauopathy and that altered adult neurogenesis should be examined as a potential marker and therapeutic target for human tauopathies.