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Suppression of neuroinflammation in forebrain-specific Cdk5 conditional knockout mice by PPARγ agonist improves
Elias Utreras, Ryusuke Hamada, Michaela Prochazkova
1Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA. ohshima@waseda.jp.
Background:
Cyclin-dependent kinase 5 (Cdk5) is essential for brain development and function, and its deregulated expression is implicated in some of neurodegenerative diseases. We reported earlier that the forebrain-specific Cdk5 conditional knockout (cKO) mice displayed an early lethality associated with neuroinflammation, increased expression of the neuronal tissue-type plasminogen activator (tPA), and neuronal migration defects.
Methods:
In order to suppress neuroinflammation in the cKO mice, we first treated these mice with pioglitazone, a PPARγ agonist, and analyzed its effects on neuronal loss and longevity. In a second approach, to delineate the precise role of tPA in neuroinflammation in these mice, we generated Cdk5 cKO; tPA double knockout (dKO) mice.
Results:
We found that pioglitazone treatment significantly reduced astrogliosis, microgliosis, neuronal loss and behavioral deficit in Cdk5 cKO mice. Interestingly, the dKO mice displayed a partial reversal in astrogliosis, but they still died at early age, suggesting that the increased expression of tPA in the cKO mice does not contribute significantly to the pathological process leading to neuroinflammation, neuronal loss and early lethality.
Conclusion:
The suppression of neuroinflammation in Cdk5 cKO mice ameliorates gliosis and neuronal loss, thus suggesting the potential beneficial effects of the PPARγ agonist pioglitazone for the treatment for neurodegenerative diseases.
Insights
Treating Cyclin-dependent kinase 5 (Cdk5) knockout mice with pioglitazone reduced neuroinflammation and neuronal loss. This suggests PPARγ agonists may benefit neurodegenerative diseases.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Cyclin-dependent kinase 5 (Cdk5) is crucial for brain development and function.
- Dysregulated Cdk5 expression is linked to neurodegenerative diseases.
- Cdk5 conditional knockout (cKO) mice exhibit early lethality, neuroinflammation, and neuronal migration defects.
Purpose of the Study:
- To investigate the therapeutic potential of pioglitazone, a PPARγ agonist, in suppressing neuroinflammation in Cdk5 cKO mice.
- To determine the role of tissue-type plasminogen activator (tPA) in the neuroinflammatory pathology of Cdk5 cKO mice.
Main Methods:
- Cdk5 cKO mice were treated with pioglitazone to assess effects on neuroinflammation, neuronal loss, and survival.
- Cdk5 cKO mice were crossed with tPA knockout mice to create double knockout (dKO) mice to study tPA's specific role.
Main Results:
- Pioglitazone treatment significantly reduced astrogliosis, microgliosis, neuronal loss, and behavioral deficits in Cdk5 cKO mice.
- dKO mice showed partial reversal of astrogliosis but still experienced early lethality.
- Increased tPA expression in cKO mice did not significantly contribute to neuroinflammation, neuronal loss, or lethality.
Conclusions:
- Suppression of neuroinflammation in Cdk5 cKO mice ameliorates gliosis and neuronal loss.
- PPARγ agonist pioglitazone shows potential for treating neurodegenerative diseases by reducing neuroinflammation.
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