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Metformin Ameliorates Synaptic Defects in a Mouse Model of AD by Inhibiting Cdk5 Activity
YaLi Wang1, JianHua Zhao2, Fang-Li Guo3
1Key Laboratory for the Brain Research of Henan Province, Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang, China.
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.
Insights
Metformin, a diabetes drug, inhibits aberrant Cdk5 activation by preventing p35 cleavage. This action rescues synaptic deficits and cognitive impairments in Alzheimer
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Cyclin-dependent kinase 5 (Cdk5) is crucial for neuronal function but its aberrant activation, due to p35 cleavage into p25, contributes to Alzheimer's disease (AD) pathology.
- Prolonged Cdk5 activation leads to synaptic depression and cognitive deficits, highlighting Cdk5 as a therapeutic target for AD.
Purpose of the Study:
- To investigate the potential of metformin, a type 2 diabetes drug, in suppressing Cdk5 hyper-activation and mitigating AD pathogenesis.
- To elucidate the molecular mechanisms underlying metformin's effects on Cdk5 activity and AD-related synaptic dysfunction.
Main Methods:
- Utilized the APP/PS1 mouse model of Alzheimer's disease.
- Assessed metformin's impact on Cdk5 hyper-activation, p35 cleavage, tau hyper-phosphorylation, and synaptic plasticity markers (spine density, GluA1 trafficking, LTP).
- Evaluated metformin's effects on spatial memory in the AD mouse model.
Main Results:
- Metformin significantly suppressed Cdk5 hyper-activation and Cdk5-dependent tau hyper-phosphorylation in the hippocampus of APP/PS1 mice.
- Identified that metformin inhibits Cdk5 hyper-activation by blocking calpain-dependent cleavage of p35 into p25.
- Chronic metformin treatment restored synaptic density, surface GluA1 trafficking, LTP expression, and spatial memory in APP/PS1 mice.
Conclusions:
- Metformin exhibits a novel therapeutic role in suppressing Cdk5 hyper-activation, thereby preventing Alzheimer's disease pathogenesis.
- Metformin demonstrates potential as a promising therapeutic agent for Alzheimer's disease.
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