The Department of Medical Education and Research, Shih Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
Neurobiol Dis. 2010 Nov;40(2):378-85. doi: 10.1016/j.nbd.2010.06.013. Epub 2010 Jul 6.
Amyloid-beta peptide (Aβ) and Tau protein are the lead constituents in the pathogenesis of Alzheimer's disease (AD). However, their inter-relationship in the disease process remains to be established. Tauopathy refers to a characteristic neurodegenerative process in AD. In tauopathy, Tau accumulates as a consequence of altered pre-mRNA splicing of tau exon 10, resulting in 3R (without exon 10)/4R (with exon 10) imbalance. We studied Aβ effects on tau exon 10 pre-mRNA splicing and relevant signaling events. This is the first demonstration of Aβ alteration of tau exon 10 splicing with an increase in 3R/4R ratio caused by reduced 4R expression. This Aβ action is causally related to its activation of GSK-3β which in turn phosphorylates SC35, an enhancer in tau exon 10 splicing. The establishment of the Aβ-GSK-3β-SC35 cascade broadens insight into development of novel strategies to modulate Aβ action on tau exon 10 splicing for possible prevention of tauopathy.
淀粉样蛋白-β肽 (Aβ) 和 Tau 蛋白是阿尔茨海默病 (AD) 发病机制中的主要成分。然而，它们在疾病过程中的相互关系仍有待确定。Tau 病是 AD 中一种特征性的神经退行性过程。在 Tau 病中，Tau 蛋白作为 Tau 外显子 10 前体 mRNA 剪接改变的结果而积累，导致 3R（无外显子 10）/4R（有外显子 10）失衡。我们研究了 Aβ 对 Tau 外显子 10 前体 mRNA 剪接和相关信号事件的影响。这是首次证明 Aβ 通过降低 4R 表达来改变 Tau 外显子 10 的剪接，导致 3R/4R 比值增加。Aβ 的这种作用与它激活 GSK-3β 有关，GSK-3β 反过来又使 Tau 外显子 10 剪接中的增强子 SC35 磷酸化。Aβ-GSK-3β-SC35 级联的建立拓宽了对新型策略的理解，以调节 Aβ 对 Tau 外显子 10 剪接的作用，从而可能预防 Tau 病。
