Human Molecular Genetics Advance Access published online on November 29, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl437
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© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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, Suita, Osaka, Japan 2 Department of Preventive Medicine, Ehime University Graduate School of Medicine, Toon, Ehime, Japan 3 Department of Basic Medical Research and Education, Ehime University Graduate School of Medicine, Toon, Ehime, Japan 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 & Neurology, Discovery Research Laboratories, Shionogi & Co., Ltd., Shiga, Japan 8 Department of Psychiatry, Chubu National Hospital, Ohbu, Japan 9 Department of Psychiatry, Osaka General Medical Center, Osaka, Japan
* To whom correspondence should be addressed at: Department of Psychiatry, Osaka University Graduate School of Medicine, 2-2-D3 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel: +81-6-6879-3051, FAX: +81-6-6879-3059, E-mail: kkamino{at}psy.med.osaka-u.ac.jp
Received September 7, 2006; Revised November 13, 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 beta amyloid (Aß) in the brain. Among 417 markers spanning 33 Mbp, 22 markers showed associations with either the allele or genotype frequency (P<0.05). Logistic regression analysis with age, sex and APOE-
4 dose supported genetic risk of 17 markers, of which 8 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 (O.R=2.99 [95%C.I.: 1.72-5.19], P=0.001), while the RUNX1 gene showed a high odds ratio (O.R.=23.3 [95%C.I.: 2.76-196.5], P=0.038). DYRK1A mRNA level in the hippocampus was significantly elevated in patients with AD compared to pathological controls (P<0.01). DYRK1A mRNA level was upregulated along with an increase in Aß level in the brain of transgenic mice overproducing Aß at age 9 months. 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 Alzheimer disease.
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