Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer's disease
Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer's disease
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DOI：
10.1111/j.1471-4159.2007.05075.x
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发表时间：
2008-03-01
影响因子：
4.7
通讯作者：
Song, Woo-Joo
中科院分区：
文献类型：
--
作者：
Ryoo, Soo-Ryoon;Cho, Hyun-Jeong;Song, Woo-Joo
大多数患有唐氏综合征（DS）的个体显示出早发性阿尔茨海默病（AD），这可能是由于21号染色体片段的额外拷贝的存在。位于21号染色体上的是编码β-淀粉样蛋白（A β）前体蛋白（APP）（一种参与AD发病机制的关键蛋白）和双特异性酪氨酸（Y）磷酸化调节激酶1A（DYRK 1A）（一种在神经发育中起关键作用的脯氨酸定向蛋白激酶）的基因。在这里，我们描述了一个潜在的机制，在DS脑AD的病理调节DYRK 1A介导的磷酸化的APP。我们表明，APP磷酸化在Thr 668 DYRK 1A在体外和哺乳动物细胞。在过表达人DYRK 1A蛋白的转基因小鼠的脑中，磷酸化APP和Ab的量增加。此外，我们表明，磷酸APP以及APP和DYRK 1A的量在人类DS脑中升高。总之，这些结果揭示了在DS脑中APP和DYRK 1A之间的潜在调节联系，并表明DS中DYRK 1A的过表达可能通过APP的磷酸化在加速AD发病中发挥作用。
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 (A beta) 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 Ab 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 overexpression of DYRK1A in DS may play a role in accelerating AD pathogenesis through phosphorylation of APP.