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

• Published in: Cell death & disease Vol. 10; no. 3; p. 221
• Main Authors: Domise, Manon, Sauvé, Florent, Didier, Sébastien, Caillerez, Raphaëlle, Bégard, Séverine, Carrier, Sébastien, Colin, Morvane, Marinangeli, Claudia, Buée, Luc, Vingtdeux, Valérie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.03.2019; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 13/106; 13/51; 13/95; 14/63; 38; 45/29; 631/378/2597; 631/378/340; 631/378/87; 64/60; 96/109; 96/35; Alzheimer Disease - pathology; Alzheimer's disease; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Animals; Antibodies; Autophagy; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cognitive ability; Enzyme Activation; Immunology; Kinases; Life Sciences; Male; Memory; Mice, Inbred C57BL; Nerve Net - pathology; Neural networks; Neurodegenerative diseases; Neurons and Cognition; Phagocytosis; Phosphates; Synapses - pathology; Synaptogenesis
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1464-x

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.