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

Cell Death Dis. 2019 Mar 4;10(3):221. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Alzheimer Disease / pathology
  • Animals
  • Autophagy*
  • Enzyme Activation
  • Male
  • Mice, Inbred C57BL
  • Nerve Net / pathology*
  • Synapses / pathology*


  • AMP-Activated Protein Kinases