Ryoo Soo-Ryoon, Cho Hyun-Jeong, Lee Hye-Won, Jeong Hey Kyeong, Radnaabazar Chinzorig, Kim Yeun-Soo, Kim Min-Jeong, Son Mi-Young, Seo Hyemyung, Chung Sul-Hee, Song Woo-Joo
Graduate Program in Neuroscience, Institute for Brain Science and Technology, Inje University, Busan, South Korea.
J Neurochem. 2008 Mar;104(5):1333-44. doi: 10.1111/j.1471-4159.2007.05075.x. Epub 2007 Nov 14.
Most individuals with Down Syndrome (DS) show an early-onset of Alzheimer's disease (AD), which potentially results from the presence of an extra copy of a segment of chromosome 21. Located on chromosome 21 are the genes that encode beta-amyloid (Abeta) precursor protein (APP ), a key protein involved in the pathogenesis of AD, and dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A (DYRK1A ), a proline-directed protein kinase that plays a critical role in neurodevelopment. Here, we describe a potential mechanism for the regulation of AD pathology in DS brains by DYRK1A-mediated phosphorylation of APP. We show that APP is phosphorylated at Thr668 by DYRK1A in vitro and in mammalian cells. The amounts of phospho-APP and Abeta are increased in the brains of transgenic mice that over-express the human DYRK1A protein. Furthermore, we show that the amounts of phospho-APP as well as those of APP and DYRK1A are elevated in human DS brains. Taken together, these results reveal a potential regulatory link between APP and DYRK1A in DS brains, and suggest that the over-expression of DYRK1A in DS may play a role in accelerating AD pathogenesis through phosphorylation of APP.
大多数唐氏综合征（DS）患者会过早患上阿尔茨海默病（AD），这可能是由于21号染色体上一段片段的额外拷贝所致。位于21号染色体上的基因编码β-淀粉样蛋白（Aβ）前体蛋白（APP），这是一种参与AD发病机制的关键蛋白，以及双特异性酪氨酸（Y）磷酸化调节激酶1A（DYRK1A），一种在神经发育中起关键作用的脯氨酸定向蛋白激酶。在这里，我们描述了一种由DYRK1A介导的APP磷酸化调节DS大脑中AD病理的潜在机制。我们表明，在体外和哺乳动物细胞中，APP在Thr668位点被DYRK1A磷酸化。在过度表达人类DYRK1A蛋白的转基因小鼠大脑中，磷酸化APP和Aβ的量增加。此外，我们表明在人类DS大脑中，磷酸化APP以及APP和DYRK1A的量都有所升高。综上所述，这些结果揭示了DS大脑中APP和DYRK1A之间潜在的调节联系，并表明DS中DYRK1A的过度表达可能通过APP的磷酸化在加速AD发病机制中发挥作用。
