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The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2007 Jan 01; Vol. 16 (1), pp. 15-23. Date of Electronic Publication: 2006 Nov 29. - Publication Year :
- 2007
-
Abstract
- 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 (Abeta) 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)-epsilon4 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 Abeta-level in the brain of transgenic mice, overproducing Abeta at 9 months of age. In neuroblastoma cells, Abeta 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 Abeta 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.
- Subjects :
- Aged
Aged, 80 and over
Alzheimer Disease genetics
Animals
Brain metabolism
Case-Control Studies
Cell Line, Tumor
Female
Haplotypes
Humans
Male
Mice
Mice, Transgenic
Middle Aged
Phosphorylation
Polymorphism, Single Nucleotide
Protein Serine-Threonine Kinases metabolism
Protein-Tyrosine Kinases metabolism
RNA, Messenger metabolism
Dyrk Kinases
Alzheimer Disease metabolism
Amyloid beta-Peptides biosynthesis
Chromosomes, Human, Pair 21 genetics
Down Syndrome genetics
Membrane Proteins metabolism
Protein Serine-Threonine Kinases genetics
Protein-Tyrosine Kinases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0964-6906
- Volume :
- 16
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 17135279
- Full Text :
- https://doi.org/10.1093/hmg/ddl437