中文摘要：

tau外显子10的可变剪接使得tau变异体含有3个或4个微管结合片段,分别称为3R-tau和4R-tau。正常人脑表达等量的3R-tau和4R-tau,它们的表达失衡可引起神经纤维退行性疾病。本文利用迷你tau基因,通过过表达和RNA沉默技术,研究了PKA的催化亚基（PKA-Cα）和（PKA-Cβ）对tau外显子10可变剪接的调节,发现PKA-Cα促进tau外显子10的编码,PKA-Cβ抑制外显子10的编码。这2种催化亚基在细胞内的定位也不尽相同,在HeLa细胞中PKA-Cα的定位以细胞核为主,而PKA-Cβ则以细胞浆为主。在阿尔茨海默病（AD）患者脑中PKA的活性和表达均下降,通过引起tau外显子10的可变剪接的失调,使得3R-tau和4R-tau的表达失衡,加速神经纤维退行性病变。

英文摘要：

The alternative splicing of tau exon 10 generates tau isoforms with 3 or 4 microtubule-binding repeats,named 3R-tau or 4R-tau,respectively.Adult normal human brain expresses equal level of 3R-tau and 4R-tau.Imbalance in 3R-tau and 4R-tau expressions causes neurofirbrillary degeneration.In the present study,the regulation of PKA catalytic subunit α and β on the alternative splicing of tau exon 10 by overexpression or RNA interference was determined.It was found that PKA-Cα promoted tau exon 10 inclusion and PKA-Cβ suppressed tau exon 10 inclusion.In HeLa cells,PKA-Cβ located in the peripheral of nucleus and PKA-Cβ mainly was in the cytoplasm.These results indicated that down-regulated PKA in AD brain might induce a dysregulation of tau exon 10 splicing,resulting in an imbalance and accelerating neurofibrillary degeneration of the disease.