ArticleMolecular neurobiology2019
Chronic Dyrk1 Inhibition Delays the Onset of AD-Like Pathology in 3xTg-AD Mice.
Article in Molecular neurobiology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 40 citations in OpenAlex.
- Elevated DYRK1A in Primary Tauopathies and Therapeutic Targeting with the Brain-Penetrant Inhibitor DYR533.Research square · 2026Article
- Current progress in pathway-targeted therapeutics for Alzheimer's disease: mechanistic insights and windows of opportunity.Molecular and cellular biochemistry · 2026Review
- Myricetin Suppresses Inflammatory Th17 Polarization to Mitigate Alzheimer's Disease Pathogenesis.CNS neuroscience & therapeutics · 2025Article
- Unlocking the Therapeutic Potential of the Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitors in Alzheimer's Diseases.Molecular neurobiology · 2025Review
- Glyphosate exposure exacerbates neuroinflammation and Alzheimer's disease-like pathology despite a 6-month recovery period in mice.Journal of neuroinflammation · 2024Article
- Discovering a novel dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) inhibitor and its impact on tau phosphorylation and amyloid-β formation.Journal of enzyme inhibition and medicinal chemistry · 2024Article
- GR/Ahi1 regulates WDR68-DYRK1A binding and mediates cognitive impairment in prenatally stressed offspring.Cellular and molecular life sciences : CMLS · 2024Article
- Modifying reaction time tasks parameters in the automated IntelliCage identifies heightened impulsivity and impaired attention in the 3xTg-AD model of Alzheimer's disease.Frontiers in aging neuroscience · 2024Article
- Re-Arranging the Puzzle between the Amyloid-Beta and Tau Pathology: An APP-Centric Approach.International journal of molecular sciences · 2023Review
- Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer's disease? From preclinical studies to the clinical trials.Molecular psychiatry · 2023Review
- Insights from the protein interaction Universe of the multifunctional "Goldilocks" kinase DYRK1A.Frontiers in cell and developmental biology · 2023Review
- Inhibition of Dyrk1A Attenuates LPS-Induced Neuroinflammation via the TLR4/NF-κB P65 Signaling Pathway.Inflammation · 2022Article
- DYRK1A antagonists rescue degeneration and behavioural deficits of in vivo models based on amyloid-β, Tau and DYRK1A neurotoxicity.Scientific reports · 2022Article
- The Omnipresence of DYRK1A in Human Diseases.International journal of molecular sciences · 2022Review
- Genetic Mapping of APP and Amyloid-β Biology Modulation by Trisomy 21.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Sexually dimorphic DYRK1A overexpression on postnatal day 15 in the Ts65Dn mouse model of Down syndrome: Effects of pharmacological targeting on behavioral phenotypes.Pharmacology, biochemistry, and behavior · 2022Article
- Network pharmacology identify intersection genes of quercetin and Alzheimer's disease as potential therapeutic targets.Frontiers in aging neuroscience · 2022Article
- Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview.International journal of molecular sciences · 2021Review
- DYRK1A: a down syndrome-related dual protein kinase with a versatile role in tumorigenesis.Cellular and molecular life sciences : CMLS · 2021Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
There is a critical need for new treatment approaches that can slow or prevent the progression of Alzheimer's disease (AD). Targets that act simultaneously on multiple relevant pathways could have significant therapeutic potential. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1a) phosphorylates both amyloid precursor protein (APP) and tau. Dyrk1a is upregulated in post-mortem brains of AD patients, and such elevated expression is associated with cognitive deficits. We previously demonstrated that small molecule inhibition of Dyrk1 is well-tolerated and reduces amyloid plaques and pathological forms of tau in 3xTg-AD mice if administered after formation of these pathologies. However, while insoluble forms of hyperphosphorylated tau were reduced by Dyrk1 inhibition, overt neurofibrillary tangle (NFT) pathology remained unchanged. Herein, we specifically test the hypothesis that inhibition of Dyrk1 prior to NFT formation will delay the onset of pathology. 3xTg-AD mice were treated chronically, beginning at 6 months of age, prior to NFT pathology. Mice were dosed daily for either 3 or 6 months and amyloid and tau pathology were assessed. We show that chronic Dyrk1 inhibition reduces insoluble forms of amyloid beta peptides (Aβ) and hyper-phosphorylated tau long-term and that these reductions are associated with dramatic delay in the onset of both amyloid plaques and NFTs. In addition, we show that DYR219, a potent and selective small molecule Dyrk1 inhibitor, induces degradation of Dyrk1a protein, likely contributing to the efficacy of this small molecule approach in vivo. Collectively, these results suggest that therapeutic strategies targeting tau phosphorylation will show the greatest effect if administered very early in the pathogenesis of AD.
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Registered trials
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