Anti-diabetes drug pioglitazone ameliorates synaptic defects in AD transgenic mice by inhibiting cyclin-dependent kinase5 activity.

Jinan Chen,Shenghua Li,Junrong Li,Wenshan Sun,Jaya Padmanabhan

doi:10.1371/journal.pone.0123864

Jinan Chen, Shenghua Li + Show 3 more

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https://doi.org/10.1371/journal.pone.0123864

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Journal: PloS one	Publication Date: Apr 14, 2015
Citations: 45	License type: CC BY 4.0

Affiliation: Nanjing Jiangning Hospital, Nanjing Medical University

Abstract

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that is activated by the neuron specific activators p35/p39 and plays many important roles in neuronal development. However, aberrant activation of Cdk5 is believed to be associated with the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Here in the present study, enhanced Cdk5 activity was observed in mouse models of AD; whereas soluble amyloid-β oligomers (Aβ), which contribute to synaptic failures during AD pathogenesis, induced Cdk5 hyperactivation in cultured hippocampal neurons. Inhibition of Cdk5 activity by pharmacological or genetic approaches reversed dendritic spine loss caused by soluble amyloid-β oligomers (Aβ) treatment. Interestingly, we found that the anti-diabetes drug pioglitazone could inhibit Cdk5 activity by decreasing p35 protein level. More importantly, pioglitazone treatment corrected long-term potentiation (LTP) deficit caused by Aβ exposure in cultured slices and pioglitazone administration rescued impaired LTP and spatial memory in AD mouse models. Taken together, our study describes an unanticipated role of pioglitazone in alleviating AD and reveals a potential therapeutic drug for AD curing.

Highlights

Alzheimer’s disease (AD), characterized by synaptic failures and cognitive impairment, has become a global threat to the public health [1,2]
To examine whether and how cyclin-dependent kinase 5 (Cdk5) plays a role in the synaptic dysfunctions during the pathogenesis of AD, we examined Cdk5 protein level and assessed its kinase activity by histone H1 phosphorylation via in vitro kinase assay in the APP/PS1 mutant mice
We found that Cdk5 activity was abnormally elevated in the 6 month-old mouse hippocampus without any obvious changes of its protein level (Fig 1A & 1B)

Summary

Introduction

Alzheimer’s disease (AD), characterized by synaptic failures and cognitive impairment, has become a global threat to the public health [1,2]. The fact that there are no effective clinical drugs for AD yet suggests that it is crucial to develop some new therapeutic interventions that based on aberrant cellular and molecular signaling pathways in AD. One of the signaling molecules that could be a potential therapeutic target is cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/threonine kinase. Cdk is activated by the neuron specific activators, p35 or p39; and plays many important roles in neuronal migration, dendritic development and synaptic plasticity. Deregulation, in particular, hyper-activation of Cdk is one key contributor to the pathogenesis of some neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD)[3,4]

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