酪蛋白激酶1ε在阿尔茨海默病tau病理改变中的作用

Tau is a neuronal microtubule-associated protein, the functions of which are regulated by phosphorylation. Adult human brain expresses six different tau isoforms from a single gene by alternative splicing. The exon 10 encodes the second microtubule binding repeat. Alternative splicing of exon 10 generates tau with three or four microtubule binding repeats (3R-tau or 4R-tau). 3R-tau and 4R-tau are expressed in approximately equal amounts in adult human brain. Either an increase or a decrease in 4R-tau expression leads to tauopathies. Abnormal hyperphosphorylation of tau and imbalance in 3R-tau and 4R-tau expression are two important events in tau pathology. Our preliminary data show that there was a remarkable increase of CK1ε in AD brain. Over expression of CK1ε in cells result in increased levels of tau phosphorylation at multiple sites and promoted exculsion of tau E10 leading to an increase in 3R-tau level and dysregulation of alternative splicing. Therefore, we will investigate the role of CK1ε in tau pathology in AD, including 1) CK1ε participation in tau abnormal hyperphosphorylation, 2)tau exon 10 alternative splicing regulation and hopefully could offer a unique preventive and therapeutic target in Alzheimer's disease.

Tau蛋白是中枢神经系统重要的微管相关蛋白，功能受磷酸化调节。通过可变剪接人脑表达六种tau变异体。外显子10编码与否决定tau含3或4个微管结合重复片段（3R/4R）。 成人脑表达等量3R-tau和4R-tau，其表达失衡可引起tau蛋白病。Tau蛋白异常过度磷酸化和3R-tau/4R-tau表达失衡是导致tau病理性改变的重要事件。我们预实验发现AD脑中的CK1ε明显增高，过表达CK1ε可催化tau 蛋白多个位点的磷酸化水平升高，并且可抑制tau外显子10编码，导致3R-tau/4R-tau表达失衡。 因此，我们考虑从CK1ε参与异常过度磷酸化和参与调控外显子10可变剪接这两个角度，对CK1ε在tau病理性改变中的作用进行探讨，为以tau和CK1ε作为新靶点的AD预防和治疗药物的开发开辟新途径。

Tau蛋白的过度磷酸化和tau外显子10异常可变剪接导致的3R-tau 和 4R-tau比例的失调是被认为是tau病理改变中的重要事件，然而，AD患者脑中导致病理性tau形成的分子机制不明。在本课题的研究中，我们发现酪蛋白激酶1ε在AD脑中显著增加。酪蛋白激酶1ε在细胞中的过度表达可以导致tau在多个位点磷酸化水平增加。而且，我们发现酪蛋白激酶1ε抑制tau外显子10的编码。此外，在人脑中我们发现tau的磷酸化水平以及3Rtau的表达和tau病理存在一定的相关性。酪蛋白激酶1ε在小鼠脑中的过表达可以使部分tau磷酸化位点水平增高并且损伤Y迷宫中的自发交替行为。这些数据表明，酪蛋白激酶1ε在调节tau磷酸化水平和参与tau外显子10的可变剪接中都起到作用。而AD患者脑中的酪蛋白激酶1ε的上调可能通过参与tau的过度磷酸化和外显子10的可变剪接两个途径导致tau的病理改变。