Tau Pathology Promotes the Reorganization of the Extracellular Matrix and Inhibits the Formation of Perineuronal Nets by Regulating the Expression and the Distribution of Hyaluronic Acid Synthases.
Tau Pathology Promotes the Reorganization of the Extracellular Matrix and Inhibits the Formation of Perineuronal Nets by Regulating the Expression and the Distribution of Hyaluronic Acid Synthases.
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Tau 病理学通过调节透明质酸合成酶的表达和分布来促进细胞外基质的重组并抑制神经周围网络的形成
DOI：
10.3233/jad-160804
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Zhao P
中科院分区：
文献类型：
--
作者：
Li Y;Li ZX;Jin T;Wang ZY;Zhao P
透明质酸（HA）是细胞外基质（ECM）的骨干，为基于聚集蛋白的神经周围网络（PNNs）提供生化和物理支持，PNNs与阿尔茨海默病（AD）中神经元的选择性易感性有关。在这里，我们发现HA合成酶（HASs），包括Has1、Has2和Has3，在小鼠中枢神经系统中广泛表达。所有类型的HASs均定位于神经元细胞体；只有Has1存在于神经轴突膜中。通过使用TauP301S转基因（Tg）小鼠模型，我们发现在TauP301S过表达的小鼠大脑中Has1的轴突定位被取消，并且在人类AD大脑中也观察到Has1的重新分布，这表明Has1的定位依赖于完整的微管，而微管的定位部分受tau蛋白磷酸化和去磷酸化周期的调节。此外，在TauP301S Tg小鼠脑中，Has1减少，Has3增加，导致ECM中短链HA上调。这些发现表明，在AD的进展过程中，tau病理通过破坏Has1的轴突定位，促进Has3的表达和短链HA的合成，从而打破ECM成分的平衡，促进ECM的重组，抑制海马内PNNs的形成，进而调节神经元的可塑性。
Hyaluronic acid (HA) is the backbone of the extracellular matrix (ECM) and provides biochemical and physical support to aggrecan-based perineuronal nets (PNNs), which are associated with the selective vulnerability of neurons in Alzheimer’s disease (AD). Here, we showed that HA synthases (HASs), including Has1, Has2, and Has3, were widely expressed in murine central nervous system. All types of HASs were localized to cell bodies of neurons; only Has1 existed in the membranes of neural axons. By using TauP301S transgenic (Tg) mouse model, we found that the axonal-localization of Has1 was abolished in TauP301S overexpressed mouse brain, and the redistribution of Has1 was also observed in human AD brains, suggesting that the localization of Has1 is dependent on intact microtubules which are regulated partially by the phosphorylation and dephosphorylation cycles of tau proteins. Furthermore, Has1 was reduced and Has3 was increased in TauP301S Tg mouse brain, resulting in the upregulation of shorter-chain HA in the ECM. These findings suggest that by abolishing the axonal-localization of Has1 and promoting the expression of Has3 and the synthesis of shorter-chain HA, the tau pathology breaks the balance of ECM components, promotes the reorganization of the ECM, and inhibits the formation of PNNs in the hippocampus, and then regulates neuronal plasticity during the progression of AD.