Pharmacological inhibition of cyclindependent kinase 5 modifies gene expression in mouse model of amyloid beta toxicity

• Autorzy: Czapski G.A. , Wilkaniec A. , Gassowska M. , Adamczyk A.
• Języki publikacji: EN

Abstrakty

EN

BACKGROUND AND AIMS: The prominent features of Alzheimer’s disease (AD) are accumulation of amyloid beta (Aβ) oligomers and neuroinflammatory processes. Previous data demonstrated that activation of cyclin-dependent kinase 5 (Cdk5) may be essential for pathology of AD and other neurodegenerative disorders. In this study we focused on the role of Cdk5 in controlling gene expression in the brain in experimental model of AD as well as during systemic inflammatory reaction (SIR) METHODS: Alzheimer’s Aβ toxicity and SIR were induced in mice by intracerebroventricular injection of Aβ1-42 oligomers and intraperitoneal injection of lipopolysaccharide (LPS), respectively. Roscovitine, the inhibitor of Cdk5, was administered intraperitoneally. RESULTS: Both Aβ and LPS induced an increase in Cdk5 activity in hippocampus, as evidenced by augmented formation of Cdk5 activator, p25, and enhanced phosphorylation of Cdk5. In concordance, Cdk5-related increase in phosphorylation of Gsk-3β (Ser9) and MAP tau (Ser396) was found. Moreover, we found Cdk5-dependent phosphorylation of ERK1/2 (Thr183/Tyr185) and MEF2A (Ser406), that may negatively modulate activity of transcription factors and in consequence the expression of various genes, i.a. those related to prosurvival pathways. Aβ and LPS injection evoked rapid activation of inflammation-related genes in hippocampus, Nos2, Tnfa, Il1b, Il6, Il10, whereas inhibition of Cdk5 with Roscovitine modified the level of micro RNA and augmented Aβ- and LPS-induced changes in mRNA level for several inflammationrelated genes. CONCLUSIONS: Cdk5 participates in regulation of gene expression in Aβ toxicity and in SIR. Our data suggest that modulation of Cdk5 activity may be prospective strategy for protection in neurodegenerative disorders. This study was supported by The National Science Centre grant 2011/03/B/NZ3/04549.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2015
• Tom: 75
• Numer: Supl.
• Opis fizyczny: p.S37-S38

Twórcy

autor

Czapski G.A.

• Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

autor

Wilkaniec A.

• Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

autor

Gassowska M.

• Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

autor

Adamczyk A.

• Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland