Transglutaminases derived from astrocytes accelerate amyloid-beta aggregation.
Transglutaminases derived from astrocytes accelerate amyloid-beta aggregation.
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源自星形胶质细胞的转谷氨酰胺酶加速淀粉样蛋白-β的聚集。
DOI：
10.1007/s11064-017-2258-0
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发表时间：
2017
影响因子：
4.4
通讯作者：
Yoichi Nakamura.
中科院分区：
文献类型：
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作者：
Kenji Kawabe;Katsura Takano;Mitsuaki Moriyama;Yoichi Nakamura.
在包括阿尔茨海默病（AD）在内的神经退行性疾病中已经观察到星形胶质细胞的活化。转氨酶（TG）是一种交联酶，参与细胞粘附、细胞骨架构建、细胞外基质形成等过程，其同工酶之一组织型TG（TG 2）在AD中被激活。此外，淀粉样蛋白β1−42（Aβ）是聚集的，并且聚集被检测为AD脑中的特征性病理，已知它是TG 2的底物。然而，脑中TG对Aβ聚集的贡献和来源仍有待澄清。在本研究中，我们研究了培养的大鼠胚胎大脑皮层星形胶质细胞对Aβ聚集的影响。当新鲜制备的Aβ加入培养的星形胶质细胞中7天后，Aβ单体减少，Aβ寡聚体不变。另一方面，当用星形胶质细胞条件培养液稀释Aβ单体时，Aβ寡聚体呈时间依赖性增加，TG抑制剂胱胺可阻断A β寡聚体的增加，而且当用聚集的Aβ刺激培养的星形胶质细胞时，TG 2表达显著增加。这些结果表明，星形胶质细胞可以摄取Aβ单体从脑内清除，但星形胶质细胞来源的TG可能会加速Aβ聚集，聚集的Aβ可能会增强星形胶质细胞的TG 2，在病理条件下形成恶性循环。充分控制TG在星形胶质细胞中的表达和功能将是AD病理学的重要因素。
Activation of astrocytes has been observed in neurodegenerative diseases including Alzheimer’s disease (AD). Transglutaminase (TG) is a crosslinking enzyme and contributes to cell adhesion, cytoskeleton construct, extracellular matrix formation, and so on. One of the isozymes, tissue-type TG (TG2) is reported to be activated in AD. Moreover, amyloid β1−42(Aβ), which is aggregated and the aggregation is detected as characteristic pathology in AD brain, is known to be a substrate of TG2. However, contribution and derivation of TGs in brain for Aβ aggregation remain to be clarified. In the present study, we examined the effects of cultured astrocytes prepared from rat embryonic brain cortex on Aβ aggregation. When freshly prepared Aβ was added to cultured astrocytes for 7 days, Aβ monomer decreased and Aβ oligomer unchanged. On the other hand, when Aβ monomer was diluted with astrocytes conditioned medium, Aβ oligomer increased time-dependently, and an inhibitor of TGs, cystamine, blocked it. Furthermore, when cultured astrocytes were stimulated with aggregated Aβ, TG2 expression significantly increased. These results suggest that astrocytes could uptake Aβ monomer to eliminate from brain; however, TGs derived from astrocytes might accelerate Aβ aggregation and the aggregated Aβ might enhance TG2 in astrocytes as a vicious cycle in pathological conditions. Adequate control of TGs expression and function in astrocytes would be an important factor in AD pathology.