Suppression of neuroinflammation in forebrain-specific Cdk5 conditional knockout mice by PPARγ agonist improves neuronal loss and early lethality

Elias Utreras,Satoru Takahashi,Toshio Ohshima,Michaela Prochazkova,Ashok B Kulkarni,Ryusuke Hamada,Anita Terse

doi:10.1186/1742-2094-11-28

Abstract

BackgroundCyclin-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.MethodsIn 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.ResultsWe 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.ConclusionThe 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.

Highlights

Cyclin-dependent kinase 5 (Cdk5) is essential for brain development and function, and its deregulated expression is implicated in some of neurodegenerative diseases
We had earlier observed that the neuroinflammation and neuronal loss occurred at P90 but not at P21 in Cdk5 cKO1 mice as compared to Cdk5f/f controls [10]
At P30, we observed increased GFAPpositive cells and ionized calcium binding adaptor molecule 1 (Iba1)-positive cells in the brain cortex of Cdk5 cKO1 mice (Additional file 2: Figure S2F-J); there was no apparent decrease in the neuronal nuclei NFκB (NeuN)-positive cells, indicating that neuronal loss did not occur at this age

Summary

Introduction

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 Cdk 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. Since PPARγ agonist pioglitazone has been reported to effectively suppress neuroinflammation in an Alzheimer’s disease (AD) mouse model [11] and it had beneficial effects in mouse models of multiple sclerosis (ALS) [12,13,14,15] and Parkinson’s disease (PD) [16], we treated cKO mice with pioglitazone, and analyzed its effects on longevity, neuronal loss, and studied the timing of activation of astrocytes and microglial cells by using immunofluorescence against anti-GFAP and Iba, respectively. The loss of tPA expression in the forebrain of the cKO mice did not ameliorate neuroinflammation and early lethality in these mice

Methods

Results

Discussion

Conclusion