The formation of small aggregates contributes to the neurotoxic effects of tau(45-230).
The formation of small aggregates contributes to the neurotoxic effects of tau(45-230).
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DOI：
10.1016/j.neuint.2021.105252
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发表时间：
2022-01
影响因子：
4.2
通讯作者：
Ferreira A
中科院分区：
文献类型：
--
作者：
Afreen S;Ferreira A
细胞内过度磷酸化的tau沉积通常在tau病中检测到。此外，这些聚集体似乎在这些疾病的病理生物学中起重要作用。在本研究中，我们确定了最近发现的神经毒性tau45-230片段是否也在神经退行性疾病中形成聚集体。通过在非变性条件下进行的Western blot分析，在阿尔茨海默病（AD）受试者的脑样本中检测了这种聚集体的存在。我们的研究结果表明，不同大小的tau45-230低聚物的混合物很容易在从AD受试者获得的脑样本中检测到。我们的数据还表明，tau45-230寡聚物可以被培养的海马神经元内化，主要是通过网格蛋白介导的机制，引发它们的变性。此外，体外聚集研究表明，tau45-230调节全长tau聚集，从而诱导形成更小、潜在毒性更大的这种微管相关蛋白聚集物。总之，这些数据确定了tau45-230毒性作用的其他机制。
Intracellular deposits of hyperphosphorylated tau are commonly detected in tauopathies. Furthermore, these aggregates seem to play an important role in the pathobiology of these diseases. In the present study, we determined whether the recently identified neurotoxic tau45–230 fragment also formed aggregates in neurodegenerative disorders. The presence of such aggregates was examined in brain samples obtained from Alzheimer’s disease (AD) subjects by means of Western blot analysis performed under non-denaturing conditions. Our results showed that a mixture of tau45–230 oligomers of different sizes was easily detectable in brain samples obtained from AD subjects. Our data also suggested that tau45–230 oligomers could be internalized by cultured hippocampal neurons, mainly through a clathrin-mediated mechanism, triggering their degeneration. In addition, in vitro aggregation studies showed that tau45–230 modulated full-length tau aggregation thereby inducing the formation of smaller, and potentially more toxic, aggregates of this microtubule-associated protein. Together, these data identified alternative mechanisms underlying the toxic effects of tau45–230.