Biochemistry and molecular biology of tauopathies
Biochemistry and molecular biology of tauopathies
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DOI：
10.1111/j.1440-1789.2006.00666.x
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发表时间：
2006-10-01
期刊：
影响因子：
2.3
通讯作者：
Hasegawa, Masato
中科院分区：
文献类型：
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作者：
Hasegawa, Masato
神经元或神经胶质细胞中的丝状 tau 沉积是神经退行性 tau 病的标志性病变，例如阿尔茨海默病、皮克病、皮质基底节变性和进行性核上性麻痹。对患有 tau 病的大脑中的肌氨酰不溶性 tau 进行生化分析，结果显示，不同疾病中的 tau 沉积物由不同的 tau 亚型组成（即，所有六种 tau 亚型均出现在阿尔茨海默病中，四种重复 tau 亚型出现在皮质基底节变性或进行性核上性麻痹中，三种重复 tau 亚型出现在皮克病中）。 FTDP-17 tau 基因突变的发现证实，tau 功能或表达异常足以导致过度磷酸化 tau 丝状聚集和神经变性，类似于散发性 tau 病中所见的情况。由于 tau 蛋白包涵体的数量及其区域分布与临床症状相关，因此抑制神经元或神经胶质细胞中 tau 蛋白聚集或丝形成可能会预防神经退行性变。我们研究了属于 9 个不同化学类别的 42 种化合物对 tau 丝形成的影响，发现几种吩噻嗪和多酚化合物以及一种卟啉化合物抑制 tau 丝形成。
Filamentous tau deposits in neurons or glial cells are the hallmark lesions of neurodegenerative tauopathies, such as Alzheimer's disease, Pick's disease, corticobasal degeneration and progressive supranuclear palsy. Biochemical analyses of Sarkosyl-insoluble tau from brains with tauopathies have revealed that tau deposits in different diseases consisted of different tau isoforms (i.e., all six tau isoforms occur in Alzheimer's disease, four repeat tau isoforms occur in corticobasal degeneration or progressive supranuclear palsy, and three repeat tau isoforms occur in Pick's disease). The discovery of mutations in the tau gene in FTDP-17 has established that abnormalities in tau function or expression are sufficient to cause filamentous aggregation of hyperphosphorylated tau and neurodegeneration similar to that seen in sporadic tauopathies. Because the number of tau inclusions and their regional distribution correlate with clinical symptoms, inhibition of tau aggregation or filament formation in neurons or glial cells may prevent neurodegeneration. We have investigated the effects of 42 compounds belonging to nine different chemical classes on tau filament formation, and found that several phenothiazine and polyphenol compounds, and one porphyrin compound inhibit tau filament formation.