The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between β-amyloid production and tau phosphorylation in Alzheimer disease
Open accessAbstract
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.
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Many additional genes on HSA21 modulate processes that could contribute to AD pathology in DS.
“However, many additional genes on HSA21 modulate processes that could contribute to AD pathology in DS.14,15,16”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [14]
The Discussion (page unavailable) reports AD-associated markers linked to six chromosome 21 genes, and the paper describes how DYRK1A may connect amyloid accumulation to tau phosphorylation. The other genes are discussed mainly through their known functions and genetic associations; the paper does not establish that many of them modulate processes contributing to AD pathology specifically in Down syndrome. (LLM, conf=0.83)
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“Furthermore, these data indicate that triplication of HSA21 orthologous genes can alter the neuropathology in AD mice, exacerbating a decreased neuronal density, which could contribute to the fact that 5xFAD-DP16 mice exhibit impaired spatial learning and memory relative to models of AD or DS. ,61,62 To determine whet…”
Influential
- Authors
- Kimura, R., Kamino, K., Yamamoto, M., Nuripa, A., Kida, T., Kazui, H., Hashimoto, R., Tanaka, T., Kudo, T., Yamagata, H., Tabara, Y., Miki, T., Akatsu, H., Kosaka, K., Funakoshi, E., Nishitomi, K., Sakaguchi, G., Kato, A., Hattori, H., Uema, T., & Takeda, M.
- Affiliations
- The University of Osaka (JP)
- Ehime University (JP)
- Fukushimura Hospital (JP)
- Setsunan University (JP)
- Shionogi (Japan) (JP)
- Chubu National Hospital (JP)
- Osaka Prefectural Medical Center (JP)
- Corresponding author
- Kamino, Kouzin
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-11-29
- Volume
- 16
- Issue
- 1
- Pages
- 15-23
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2125851351
- Cited by
- 281
- References
- 2
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 7 · 2023: 17 · 2022: 25 · 2021: 22 · 2020: 10 · 2019: 8 · 2018: 12 · 2017: 10 · 2016: 13 · 2015: 17 · 2014: 13 · 2013: 11 · 2012: 15
- FWCI
- 6.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Human Molecular Genetics (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Keywords
- DYRK1A, late-onset Alzheimer's disease, Down syndrome critical region, chromosome 21, amyloid-beta, tau phosphorylation, genetic association, RUNX1, Down syndrome, hippocampus, transgenic mice, neuroblastoma cells, Japanese patients
- MeSH terms
- Dyrk Kinases, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Chromosomes, Human, Pair 21, Down Syndrome, Female, Haplotypes, Humans, Male, Membrane Proteins, Mice, Transgenic, Middle Aged, Phosphorylation, Protein-Tyrosine Kinases, RNA, Messenger, Case-Control Studies, Amyloid beta-Peptides, tau Proteins, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Cell Line, Tumor, Mice
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