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Cited by 71Down syndrome and intellectual disability researchAlzheimer's disease research and treatmentsCholinesterase and Neurodegenerative Diseases

DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives

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Neumann, Fernanda, Gourdain, Stéphanie, Albac, Christelle, Dekker, Alain D., Bui, Linh Chi, Dairou, Julien, Schmitz-Afonso, Isabelle, Hue, Nathalie +8 more·2018·Scientific Reports
DOI 10.1038/s41598-018-20984-zPMC PMC5809559
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Abstract

Inhibition of DYRK1A kinase, produced by chromosome 21 and consequently overproduced in trisomy 21 subjects, has been suggested as a therapeutic approach to treating the cognitive deficiencies observed in Down syndrome (DS). We now report the synthesis and potent DYRK1A inhibitory activities of fluoro derivatives of 3,5-di(polyhydroxyaryl)-7-azaindoles (F-DANDYs). One of these compounds (3-(4-fluorophenyl)-5-(3,4-dihydroxyphenyl)-1 H-pyrrolo[2,3-b]pyridine, 5a) was selected for in vivo studies of cognitive rescuing effects in a standard mouse model of DS (Ts65Dn line). Using the Morris water maze task, Ts65Dn mice treated i.p. with 20 mg/kg of 5a performed significantly better than Ts65Dn mice treated with placebo, confirming the promnesiant effect of 5a in the trisomic mice. Overall, these results demonstrate for the first time that selective and competitive inhibition of DYRK1A kinase by the F-DANDY derivative 5a may provide a viable treatment strategy for combating the memory and learning deficiencies encountered in DS.

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  • Some genes triplicated in Dp16 mice, including Dyrk1a, Usp25, S100b, Rcan1, and the Ifnrs, could contribute to cognitive dysfunction.

    “indicating that some genes triplicated in Dp16 mice could contribute to cognitive dysfunction, including Dyrk1a, Usp25, S100b, Rcan1, and the Ifnrs.”

    From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [77]

    The Introduction links elevated DYRK1A levels in Down syndrome to cognitive deficits, and the Behavioral Studies with Compound 5a section identifies Dyrk1a in the trisomic region of Ts65Dn mice. The paper studies Ts65Dn, not Dp16, and the passages do not support the proposed roles of Usp25, S100b, Rcan1, or the Ifnrs. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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Authors
Neumann, F., Gourdain, S., Albac, C., Dekker, A. D., Bui, L. C., Dairou, J., Schmitz-Afonso, I., Hue, N., Rodrigues-Lima, F., Delabar, J. M., Potier, M.-C., Le Caër, J.-P., Touboul, D., Delatour, B., Cariou, K., & Dodd, R. H.
Affiliations
  • Université Paris-Sud (FR)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
Dodd, Robert H.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2018-02-12
Volume
8
Issue
1
Pages
2859-2859
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-018-20984-z
PMC
PMC5809559
OpenAlex
W2796873125
Cited by
71
References
2
Citations by year
2026: 11 · 2025: 8 · 2024: 9 · 2023: 8 · 2022: 6 · 2021: 10 · 2020: 8 · 2019: 7 · 2018: 4
FWCI
6.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
Funders
  • Agence Nationale de la Recherche (ANR-10-IAIHU06, ANR-11 IDEX-0003-01, ANR-11-IDEX-0003, 10-IAIHU-06, ANR-11-IDEX, 10-LABX-33, ANR-10, ANR-10-LABX, ANR-10-IAHU-0006, ANR-10-LABX-0033, ANR‐10‐LABX‐33)
  • Fondation Jérôme Lejeune
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • Centre National de la Recherche Scientifique (ANR-10-LABX-33, 11-IDEX-0003, ANR-11-IDEX-0003-01)
  • Université Paris Diderot
  • Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique (ANR-10-LABX-33, ANR-11-IDEX-0003-01)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
Down syndrome, pyrrolo[2,3-b]pyridine, Ts65Dn mouse model, learning and memory impairment, drug synthesis
MeSH terms
Dyrk Kinases, Animals, Cognition, Disease Models, Animal, Down Syndrome, Humans, Injections, Intraperitoneal, Learning Disabilities, Memory Disorders, Protein-Tyrosine Kinases, Pyridines, Molecular Structure, Protein Serine-Threonine Kinases, Maze Learning, Protein Kinase Inhibitors, Mice

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