Metformin Ameliorates Synaptic Defects in a Mouse Model of AD by Inhibiting Cdk5 Activity.

Yali Wang,Shouqing Liu,Xiahuan Gao,Luyi Zhang,Jianhua Zhao,Xin Yang,Libing Fan,Jiangang Wang,Xinfeng Yang,Xine Xie,Fang-Li Guo,Yuxiao Ye

doi:10.3389/fncel.2020.00170

Abstract

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that is activated by the neuron-specific activators p35/p39 and plays important roles in neuronal development, synaptic plasticity, and cognitive behavior. However, the proteolytic cleavage of p35 to p25 leads to prolonged and aberrant Cdk5 activation and results in synaptic depression, highly mimicking the early pathology of Alzheimer’s disease (AD). Therefore, Cdk5 inhibition is a potential promising strategy for AD drug development. Here in the present study, we showed that metformin, the most widely used drug for type 2 diabetes, suppressed Cdk5 hyper-activation and Cdk5-dependent tau hyper-phosphorylation in the APP/PS1 mouse hippocampus. We also identified the underlying molecular and cellular mechanism that metformin prevented Cdk5 hyper-activation by inhibiting the calpain-dependent cleavage of p35 into p25. Moreover, chronic metformin treatment rescued the core phenotypes in APP/PS1 mice as evidenced by restored spine density, surface GluA1 trafficking, Long-term potentiation (LTP) expression, and spatial memory. Altogether our study discovered an unidentified role of metformin in suppressing Cdk5 hyper-activation and thus preventing AD pathogenesis and suggested that metformin is a potential promising AD therapeutic drug.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by synaptic depression, synapse loss, and cognitive impairment
Consistent with previous studies which showed that Cyclin-dependent kinase 5 (Cdk5) signaling pathway is hyperactivated in APP/PS1 mice (Qu et al, 2011; Fu et al, 2014; Chen et al, 2015), Cdk5 activity was elevated in the adult APP/PS1 mouse hippocampus
We combined pharmacological, molecular and cellular, electrophysiological, and behavioral techniques to study the roles of Cdk5 signaling in AD pathogenesis and how chronic metformin treatment had beneficial effects on the synaptic malfunctions and the cognitive defects in the APP/PS1 mice through the regulation of the Cdk5 signaling pathway

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by synaptic depression, synapse loss, and cognitive impairment. It has become the sixth leading cause of death and is a global threat to public health. This disease afflicts ∼44 million people worldwide and accounts for ∼605 billion in medical expenses in 2019. Many drugs that target amyloid beta (Aβ) deposits failed in preclinical or clinical trials. All these facts drove us to look carefully into the pathophysiological mechanisms underlying the synaptic failures in AD and hope to find out some promising targets for drug development

Methods

Results

Conclusion