LPS-Induced Inflammation Abolishes the Effect of DYRK1A on IkB Stability in the Brain of Mice.
Alizée LatourYuchen GuNadim KassisFabrice DaubigneyCatherine ColinBlandine GausserèsSandrine MiddendorpJean-Louis PaulValérie HindiéJean-Christophe RainJean-Maurice DelabarEugene YuMariona ArbonesMichel MallatNathalie JanelPublished in: Molecular neurobiology (2018)
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.
Keyphrases
- toll like receptor
- inflammatory response
- lps induced
- early onset
- oxidative stress
- signaling pathway
- lipopolysaccharide induced
- protein protein
- end stage renal disease
- binding protein
- magnetic resonance
- type diabetes
- poor prognosis
- magnetic resonance imaging
- computed tomography
- high fat diet induced
- chronic kidney disease
- insulin resistance
- transcription factor
- mild cognitive impairment
- small molecule
- newly diagnosed
- resting state
- white matter
- long non coding rna
- ejection fraction
- multiple sclerosis
- adipose tissue
- brain injury
- combination therapy
- induced apoptosis
- spinal cord injury
- protein kinase