DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease

Topic: Brain proteins, microglia and lab models

Most individuals with Down syndrome show early onset of Alzheimer disease (AD), resulting from the extra copy of chromosome 21. Located on this chromosome is a gene that encodes the dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). One of the pathological hallmarks in AD is the presence of neurofibrillary tangles (NFTs), which are insoluble deposits that consist of abnormally hyperphosphorylated Tau. Previously it was reported that Tau at the Thr-212 residue was phosphorylated by Dyrk1A in vitro. To determine the physiological significance of this phosphorylation, an analysis was made of the amount of phospho-Thr-212-Tau (pT212) in the brains of transgenic mice that overexpress the human DYRK1A protein (DYRK1A TG mice) that we recently generated. A significant increase in the amount of pT212 was found in the brains of DYRK1A transgenic mice when compared with age-matched littermate controls. We further examined whether Dyrk1A phosphorylates other Tau residues that are implicated in NFTs. We found that Dyrk1A also phosphorylates Tau at Ser-202 and Ser-404 in vitro. Phosphorylation by Dyrk1A strongly inhibited the ability of Tau to promote microtubule assembly. Following this, using mammalian cells and DYRK1A TG mouse brains, it was demonstrated that the amounts of phospho-Ser-202-Tau and phospho-Ser-404-Tau are enhanced when DYRK1A amounts are high. These results provide the first in vivo evidence for a physiological role of DYRK1A in the hyperphosphorylation of Tau and suggest that the extra copy of the DYRK1A gene contributes to the early onset of AD.

Key findings

• A significant increase in the amount of pT212 was found in the brains of DYRK1A transgenic mice when compared with age-matched littermate controls.
• We found that Dyrk1A also phosphorylates Tau at Ser-202 and Ser-404 in vitro.
• Following this, using mammalian cells and DYRK1A TG mouse brains, it was demonstrated that the amounts of phospho-Ser-202-Tau and phospho-Ser-404-Tau are enhanced when DYRK1A amounts are high.
• These results provide the first in vivo evidence for a physiological role of DYRK1A in the hyperphosphorylation of Tau and suggest that the extra copy of the DYRK1A gene contributes to the early onset of AD.

Why it matters

This study found that the DYRK1A protein can add phosphate groups to tau at several sites, which reduced tau's ability to support microtubules, in mice and cells. These are laboratory and animal findings that suggest a possible mechanism linking Down syndrome and Alzheimer's disease, but they do not establish a treatment.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1074/jbc.m707358200
• PubMed: 17906291
• Original source →
• Free full text: Journal of Biological Chemistry →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{ryoo2007-17906291,
  author  = {Ryoo, SR. and Jeong, H. K. and Radnaabazar, C. and Yoo, J. J. and Cho, H. J. and Lee, H. W. and Kim, I. S. and Cheon, Y. H. and others},
  title   = {{DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease}},
  journal = {The Journal of biological chemistry},
  year    = {2007},
  doi     = {10.1074/jbc.m707358200},
  pmid    = {17906291},
  url     = {https://doi.org/10.1074/jbc.m707358200}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Amyloid plaque core protein in Alzheimer disease and Down syndrome Proceedings of the National Academy of Sciences of the United States of America · 1985-06-01 · usefulness score 56/100 · Down syndrome and Alzheimer's
• A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads Acta neuropathologica · 1994-01-01 · usefulness score 53/100 · Brain tissue and pathology
• Down syndrome phenotypes: the consequences of chromosomal imbalance Proceedings of the National Academy of Sciences of the United States of America · 1994-05-01 · usefulness score 52/100 · Down syndrome and Alzheimer's
• Constitutive Dyrk1A is abnormally expressed in Alzheimer disease, Down syndrome, Pick disease, and related transgenic models Neurobiology of disease · 2005-11-01 · usefulness score 44/100 · Down syndrome and Alzheimer's

Later studies that cite this one

19 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.

• Dementia in Down syndrome: unique insights for Alzheimer disease research Nature reviews. Neurology · 2019-03-01 · usefulness score 60/100 · Down syndrome and Alzheimer's
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• Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome Translational neurodegeneration · 2018-11-06 · usefulness score 47/100 · Down syndrome and Alzheimer's
• Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2008-05-28 · usefulness score 46/100 · Down syndrome and Alzheimer's
• mTOR in Down syndrome: Role in Aß and tau neuropathology and transition to Alzheimer disease-like dementia Free radical biology & medicine · 2017-08-12 · usefulness score 45/100 · Down syndrome and Alzheimer's
• A novel DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro Journal of neurochemistry · 2015-01-26 · usefulness score 45/100 · Down syndrome and Alzheimer's
• Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome Journal of neuropathology and experimental neurology · 2011-01-01 · usefulness score 43/100 · Down syndrome and Alzheimer's
• The role of DYRK1A in neurodegenerative diseases The FEBS journal · 2010-12-13 · usefulness score 43/100 · Down syndrome and Alzheimer's

Related studies in Down syndrome and Alzheimer's

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• Regulation of RCAN1 protein activity by Dyrk1A protein-mediated phosphorylation The Journal of biological chemistry · 2011-09-30 · usefulness score 38/100
• Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome The Journal of biological chemistry · 2008-07-24 · usefulness score 46/100
• β-carboline compounds, including harmine, inhibit DYRK1A and tau phosphorylation at multiple Alzheimer's disease-related sites PloS one · 2011-05-06 · usefulness score 40/100

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