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Neuronal AMP-activated protein kinase hyper-activation induces synaptic loss by an autophagy-mediated process

Abstract : Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic loss that leads to the development of cognitive deficits. Synapses are neuronal structures that play a crucial role in memory formation and are known to consume most of the energy used in the brain. Interestingly, AMP-activated protein kinase (AMPK), the main intracellular energy sensor, is hyper-activated in degenerating neurons in several neurodegenerative diseases, including AD. In this context, we asked whether AMPK hyper-activation could influence synapses' integrity and function. AMPK hyper-activation in differentiated primary neurons led to a time-dependent decrease in pre- and post-synaptic markers, which was accompanied by a reduction in synapses number and a loss of neuronal networks functionality. The loss of post-synaptic proteins was mediated by an AMPK-regulated autophagy-dependent pathway. Finally, this process was also observed in vivo, where AMPK hyper-activation primed synaptic loss. Overall, our data demonstrate that during energetic stress condition, AMPK might play a fundamental role in the maintenance of synaptic integrity, at least in part through the regulation of autophagy. Thus, AMPK might represent a potential link between energetic failure and synaptic integrity in neurodegenerative conditions such as AD.
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Submitted on : Tuesday, November 5, 2019 - 1:41:03 PM
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Manon Domise, Florent Sauvé, Sébastien Didier, Raphaëlle Caillerez, Séverine Bégard, et al.. Neuronal AMP-activated protein kinase hyper-activation induces synaptic loss by an autophagy-mediated process. Cell Death and Disease, Nature Publishing Group, 2019, 10 (3), pp.221. ⟨10.1038/s41419-019-1464-x⟩. ⟨inserm-02348480⟩

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