Astrocyte-specific IKK2 activation in mice is sufficient to induce neuroinflammation but does not increase susceptibility to MPTP

Neurobiology of Disease

卷:48

Michael Lattke¹  Patrick Oeckl²  Boris Ferger³  Thomas Wirth³  Bernd Baumann³ 

[1] Co. KG, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany;

[2] CNS Diseases Research, Boehringer Ingelheim Pharma GmbH &

[3] Institute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany;

关键词: Neuroinflammation;    IKK2;    NF-κB;    Astrocytes;    MPTP;    Parkinson's disease;   

DOI  :  

来源: DOAJ

【 摘 要 】

A key regulator of inflammatory gene expression is the transcription factor NF-κB that is controlled by the IκB proteins. We used a transgenic mouse model expressing a constitutively active IκB-kinase-2 (IKK2-CA) in astrocytes under control of the human glial fibrillary acidic protein promotor (IKK2-mice) to investigate neuroinflammation, proinflammatory cytokine expression, microglial activation and a potential enhanced susceptibility to the neurotoxin MPTP (4×10 mg/kg). Readouts included the determination of cytokines, striatal dopamine (DA), nigral tyrosine hydroxylase (TH) positive neurons, microglial activation and motor activity.IKK2-CA expression in astrocytes conditionally induced by the tet-off system resulted in a widespread neuroinflammation indicated by the increased expression of inflammatory cytokines and the presence of activated microglia and astrogliosis. Additionally, striatal DA concentrations but not nigral TH-positive neurons were reduced in IKK2-mice by 20%. Motor activity of IKK2-mice was not affected. Surprisingly, there was a similar reduction in striatal DA concentrations and the number of nigral TH-positive neurons in IKK2 and control mice after MPTP treatment.In conclusion, although naïve IKK2-mice showed reduced striatal DA concentrations and an increase in inflammatory markers in the brain, a higher susceptibility to MPTP was not observed. This finding argues against a prominent role of astrocyte specific, IKK2-mediated neuroinflammation in MPTP-induced neurodegeneration.

【 授权许可】

Unknown