The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between β-amyloid production and tau phosphorylation in Alzheimer disease
The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between β-amyloid production and tau phosphorylation in Alzheimer disease
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DOI：
10.1093/hmg/ddl437
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发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Takeda, Masatoshi
中科院分区：
文献类型：
--
作者：
Kimura, Ryo;Kamino, Kouzin;Takeda, Masatoshi
我们使用374名日本患者和375名基于人群的对照，扫描了整个21号染色体，以评估与迟发性阿尔茨海默病（AD）的遗传关联，因为已知21三体与大脑中β-淀粉样蛋白（A β）的早期沉积有关。在417个33 Mb的标记中，有22个标记与等位基因或基因型频率相关（P < 0.05）。对年龄、性别和载脂蛋白E（APOE）-14剂量的Logistic回归分析支持17个标记物的遗传风险，其中8个标记物与SAMSN 1、PRSS 7、NCAM 2、RUNX 1、DYRK 1A和KCNJ 6基因连锁。在逻辑回归中，DYRK 1A双特异性酪氨酸调节激酶1A基因位于唐氏综合征临界区，其差异有统计学意义[OR 52.99（95%CI：1.72-5.19），P = 0.001]，而RUNX 1基因显示高优势比[OR 5 23.3（95%CI：2.76-196.5），P = 0.038]。AD患者海马DYRK 1A mRNA表达水平明显高于病理对照组（P < 0.01）。DYRK 1A mRNA水平随着转基因小鼠脑中A β水平的增加而沿着上调，在9月龄时过量产生A β。在神经母细胞瘤细胞中，A β诱导DYRK 1A转录物的增加，这也导致在tau过表达的情况下在Thr 212处的tau磷酸化。因此，抗体负载导致DYRK 1A转录上调，进一步导致tau磷酸化。我们的研究结果表明，DYRK 1A可能是AD中β-淀粉样蛋白产生和tau磷酸化之间的关键分子。
We scanned throughout chromosome 21 to assess genetic associations with late-onset Alzheimer disease (AD) using 374 Japanese patients and 375 population-based controls, because trisomy 21 is known to be associated with early deposition of beta-amyloid (A beta) in the brain. Among 417 markers spanning 33 Mb, 22 markers showed associations with either the allele or the genotype frequency (P < 0.05). Logistic regression analysis with age, sex and apolipoprotein E (APOE)-14 dose supported genetic risk of 17 markers, of which eight markers were linked to the SAMSN1, PRSS7, NCAM2, RUNX1, DYRK1A and KCNJ6 genes. In logistic regression, the DYRK1A (dual-specificity tyrosine-regulated kinase 1A) gene, located in the Down syndrome critical region, showed the highest significance [OR 5 2.99 (95% CI: 1.72-5.19), P = 0.001], whereas the RUNX1 gene showed a high odds ratio [OR 5 23.3 (95% CI: 2.76-196.5), P = 0.038]. DYRK1A mRNA level in the hippocampus was significantly elevated in patients with AD when compared with pathological controls (P < 0.01). DYRK1A mRNA level was upregulated along with an increase in the A beta-level in the brain of transgenic mice, overproducing A beta at 9 months of age. In neuroblastoma cells, A beta induced an increase in the DYRK1A transcript, which also led to tau phosphorylation at Thr 212 under the overexpression of tau. Therefore, the upregulation of DYRK1A transcription results from Ab loading, further leading to tau phosphorylation. Our result indicates that DYRK1A could be a key molecule bridging between beta-amyloid production and tau phosphorylation in AD.