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

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...

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Detalles Bibliográficos
Autores principales: Domise, Manon, Sauvé, Florent, Didier, Sébastien, Caillerez, Raphaëlle, Bégard, Séverine, Carrier, Sébastien, Colin, Morvane, Marinangeli, Claudia, Buée, Luc, Vingtdeux, Valérie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399353/
https://www.ncbi.nlm.nih.gov/pubmed/30833547
http://dx.doi.org/10.1038/s41419-019-1464-x
Descripción
Sumario: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.