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LPS-Induced Inflammation Abolishes the Effect of DYRK1A on IkB Stability in the Brain of Mice

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Abstract

Down syndrome is characterized by premature aging and dementia with neurological features that mimic those found in Alzheimer’s disease. This pathology in Down syndrome could be related to inflammation, which plays a role in other neurodegenerative diseases. We previously found a link between the NFkB pathway, long considered a prototypical proinflammatory signaling pathway, and the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). DYRK1A is associated with early onset of Alzheimer’s disease in Down syndrome patients. Here, we sought to determine the role of DYRK1A on regulation of the NFkB pathway in the mouse brain. We found that over-expression of Dyrk1A (on a C57BL/6J background) stabilizes IκBα protein levels by inhibition of calpain activity and increases cytoplasmic p65 sequestration in the mouse brain. In contrast, Dyrk1A-deficient mice (on a CD1 background) have decreased IκBα protein levels with an increased calpain activity and decreased cytoplasmic p65 sequestration in the brain. Taken together, our results demonstrate a role of DYRK1A in regulation of the NFkB pathway. However, decreased IκBα and DYRK1A protein levels associated with an increased calpain activity were found in the brains of mice over-expressing Dyrk1A after lipopolysaccharide treatment. Although inflammation induced by lipopolysaccharide treatment has a positive effect on calpastatin and a negative effect on DYRK1A protein level, a positive effect on microglial activation is maintained in the brains of mice over-expressing Dyrk1A.

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Acknowledgements

We acknowledge the platform accommodation and animal testing of the animal house at the Institute Jacques-Monod (University Paris Diderot) and the FlexStation3 and PIC2 Facilities of the Functional and Adaptative Biology (BFA) laboratory.

Funding

This work was supported by the Fondation Jerome Lejeune (grant number 2017a-1634).

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Author notes

  1. Alizée Latour and Yuchen Gu contributed equally to this work.

Authors and Affiliations

  1. Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative (BFA), Université Paris Diderot, UMR 8251, 75205, Paris, France

    Alizée Latour, Yuchen Gu, Nadim Kassis, Fabrice Daubigney, Blandine Gausserès, Sandrine Middendorp, Jean-Maurice Delabar & Nathalie Janel

  2. Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France

    Catherine Colin & Michel Mallat

  3. AP-HP, Hôpital Européen Georges Pompidou, Service de Biochimie, 75015, Paris, France

    Jean-Louis Paul

  4. HYBRIGENICS Services SAS, Paris, France

    Valérie Hindié & Jean-Christophe Rain

  5. Children’s Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Eugene Yu

  6. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain

    Mariona Arbones

  7. Institut de Biologia Molecular de Barcelona (IBMB), 08028, Barcelona, Spain

    Mariona Arbones

  8. Laboratoire BFA, Université Paris Diderot – Paris 7, Case 7104, 3 rue Marie-Andrée Lagroua Weill Hallé, 75205, Paris Cedex 13, France

    Nathalie Janel

Authors
  1. Alizée Latour
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  2. Yuchen Gu
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Contributions

AL, YG, and NJ designed the study; AL, YG, NK, FD, CC, and BG performed experiments; SM, VH, JCR, and SM performed yeast two-hybrid analysis; JLP performed HPLC analysis; NJ, AL, YG, JLP, JMD, EY, MA, and MM analyzed the data; NJ and AL wrote the paper; NJ and MM correct the manuscript.

Corresponding author

Correspondence to Nathalie Janel.

Ethics declarations

All procedures were carried out in accordance with the ethical standards of French and European regulations (European Communities Council Directive, 86/609/EEC). Official authorization from the French Ministry of Agriculture was granted to perform research and experiments on animals (authorization number 75–369), and the experimental protocol was approved by the institutional animal care and use committee of the Paris Diderot University (CEEA40).

Conflict of Interest

The authors declare that they have no conflict of interest.

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Latour, A., Gu, Y., Kassis, N. et al. LPS-Induced Inflammation Abolishes the Effect of DYRK1A on IkB Stability in the Brain of Mice. Mol Neurobiol 56, 963–975 (2019). https://doi.org/10.1007/s12035-018-1113-x

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