Journal Article

The <i>DYRK1A</i> gene, encoded in chromosome 21 Down syndrome critical region, bridges between β-amyloid production and tau phosphorylation in Alzheimer disease

Ryo Kimura, Kouzin Kamino, Mitsuko Yamamoto, Aidaralieva Nuripa, Tomoyuki Kida, Hiroaki Kazui, Ryota Hashimoto, Toshihisa Tanaka, Takashi Kudo, Hidehisa Yamagata, Yasuharu Tabara, Tetsuro Miki, Hiroyasu Akatsu, Kenji Kosaka, Eishi Funakoshi, Kouhei Nishitomi, Gaku Sakaguchi, Akira Kato, Hideyuki Hattori, Takeshi Uema and Masatoshi Takeda

in Human Molecular Genetics

Volume 16, issue 1, pages 15-23
Published in print January 2007 | ISSN: 0964-6906
Published online November 2006 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddl437
The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between β-amyloid production and tau phosphorylation in Alzheimer disease

Show Summary Details

Preview

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 β-amyloid (Aβ) 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)-ε4 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 Aβ-level in the brain of transgenic mice, overproducing Aβ at 9 months of age. In neuroblastoma cells, Aβ 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 Aβ loading, further leading to tau phosphorylation. Our result indicates that DYRK1A could be a key molecule bridging between β-amyloid production and tau phosphorylation in AD.

Journal Article.  5428 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.