All tauopathies, including Alzheimer’s disease (AD), are characterized by the intracellular accumulation of abnormal forms of tau protein in neurons and glial cells, which negatively affect microtubule stability. Under physiological conditions, tubulin-associated unit (Tau) protein is intrinsically disordered, almost without secondary structure, and is not prone to aggregation. In AD, it assembles, and forms paired helical filaments (PHFs) that further build-up neurofibrillary tangles (NFTs). Aggregates are composed of hyperphosphorylated tau protein that is more prone to aggregation. The pathology of AD is also linked to disturbed copper homeostasis, which promotes oxidative stress (OS). Copper imbalance is widely observed in AD patients. Deregulated copper ions may initiate and exacerbate tau hyperphosphorylation and formation of β-sheet-rich tau fibrils that ultimately contribute to synaptic failure, neuronal death, and cognitive decline observed in AD patients. The present review summarizes factors affecting the process of tau aggregation, conformational changes of small peptide sequences in the microtubule-binding domain required for these motifs to act as seeding sites in aggregation, and the role of copper in OS induction, tau hyperphosphorylation and tau assembly. A better understanding of the various factors that affect tau aggregation under OS conditions may reveal new targets and novel pharmacological approaches for the therapy of AD.

所有的tauopathies，包括阿尔茨海默氏病（AD），都以神经元和神经胶质细胞中异常形式的tau蛋白在细胞内的积累为特征，这会对微管的稳定性产生负面影响。在生理条件下，微管蛋白相关单位（Tau）蛋白本质上是无序的，几乎没有二级结构，并且不易于聚集。在AD中，它会组装并形成成对的螺旋丝（PHF），从而进一步形成神经原纤维缠结（NFT）。聚集体由更易于聚集的高磷酸化tau蛋白组成。AD的病理学也与铜稳态紊乱有关，铜稳态促进了氧化应激（OS）。在AD患者中广泛观察到铜不平衡。失调的铜离子可能会引发并加剧tau过度磷酸化和形成富含β-sheet的tau原纤维，最终导致AD患者中出现的突触衰竭，神经元死亡和认知能力下降。本综述总结了影响tau聚集过程的因素，这些基序在聚集中充当种子位点所需的微管结合域中小肽序列的构象变化，以及铜在OS诱导，tau过磷酸化和tau组装中的作用。 。对OS条件下影响tau聚集的各种因素的更好理解可能会揭示治疗AD的新靶点和新药理学方法。本综述总结了影响tau聚集过程的因素，这些基序在聚集中充当种子位点所需的微管结合域中小肽序列的构象变化，以及铜在OS诱导，tau过磷酸化和tau组装中的作用。 。对OS条件下影响tau聚集的各种因素的更好理解可能会揭示治疗AD的新靶点和新药理学方法。本综述总结了影响tau聚集过程的因素，这些基序在聚集中充当种子位点所需的微管结合域中小肽序列的构象变化，以及铜在OS诱导，tau过磷酸化和tau组装中的作用。 。对OS条件下影响tau聚集的各种因素的更好理解可能会揭示治疗AD的新靶点和新药理学方法。