Human Molecular Genetics Advance Access originally published online on November 29, 2006
Human Molecular Genetics 2007 16(1):15-23; doi:10.1093/hmg/ddl437
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The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between ß-amyloid production and tau phosphorylation in Alzheimer disease
1 Department of Psychiatry, Osaka University Graduate School of Medicine, 2-2-D3 Yamadaoka, Suita, Osaka 565-0871, Japan, 2 Department of Preventive Medicine, 3 Department of Basic Medical Research and Education and 4 Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon, Ehime, Japan, 5 Choju Medical Institute, Fukushimura Hospital, Toyohashi, Aichi, Japan, 6 Department of Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan, 7 Pain and Neurology, Discovery Research Laboratories, Shionogi & Co., Ltd, Shiga, Japan, 8 Department of Psychiatry, Chubu National Hospital, Ohbu, Japan and 9 Department of Psychiatry, Osaka General Medical Center, Osaka, Japan
* To whom correspondence should be addressed. Tel: +81 668793051; Fax: +81 668793059; Email: kkamino{at}psy.med.osaka-u.ac.jp
Received September 7, 2006; Accepted November 13, 2006
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 ß-amyloid (Aß) 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)-
4 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 = 2.99 (95% CI: 1.72–5.19), P = 0.001], whereas the RUNX1 gene showed a high odds ratio [OR = 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 Aß-level in the brain of transgenic mice, overproducing Aß at 9 months of age. In neuroblastoma cells, Aß induced an increase in the DYRK1A transcript, which also led to tau phosphorylation at Thr212 under the overexpression of tau. Therefore, the upregulation of DYRK1A transcription results from Aß loading, further leading to tau phosphorylation. Our result indicates that DYRK1A could be a key molecule bridging between ß-amyloid production and tau phosphorylation in AD.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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