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

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.

Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

“…The hippocampus is also one of the major brain regions affected by AD, in which hippocampal synaptic transmission is impaired [ 32 ]. Met has been demonstrated to ameliorate synaptic, memory and cognitive deficits in rodent models of AD [ 12 , 33 , 34 , 35 ]. However, there are few reports about Met effects on synaptic transmission.…”

“…Furthermore, improvements in language and cognitive behaviors were observed in a small sample size of Met-treated FXS patients [ 8 , 9 , 10 ]. In some Alzheimer’s disease (AD) mice models, Met attenuated amyloid plaque deposition and improved learning and memory [ 11 , 12 , 13 , 14 ]. Met also showed neuroprotective effects on dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-modeled mice of Parkinson’s disease (PD) [ 15 , 16 ].…”

Metabolic Aspects of Adenosine Functions in the Brain

“…When the effect of metformin, a known activator of AMPK and a drug used for the treatment of type 2 diabetes, has been investigated on cognition deficits, some studies have shown an aggravating effect (Imfeld et al, 2012;Wennberg et al, 2018), whereas others reported a preventive one (Ng et al, 2014;Shi et al, 2019). Metformin has been shown to have a positive effect on AD mouse model (Wang et al, 2020). Recently it has been investigated the possible role of the AMPK isozymes in these conflicting results using mouse models of AD (Zimmermann et al, 2020).…”

Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders

“…Metformin attenuated spatial memory deficits, neuron loss in the hippocampus, decreased Aβ plaque load and chronic inflammation in the hippocampus and cortex, and enhanced neurogenesis in the APP/PS1 mice, mouse model of AD( Ou et al, 2018 ; Chen et al, 2021 ). Metformin also restored spine density, surface AMPA subunit GluA1 trafficking, LTP expression and spatial memory in the APP/PS1 mouse by inhibiting cyclin-dependent kinase 5 hyper-activation and cyclin-dependent kinase 5-dependent tau hyperactivation( Wang et al, 2020 ). Furthermore, metformin could activate AMPK and insulin-degrading enzyme in the brain of APP/PS 1 mice, which might be the key neuroprotection mechanism of metformin( Lu et al, 2020 ).…”