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Curr Biol. 2019 Feb 4;29(3):435-448.e8. doi: 10.1016/j.cub.2018.12.021. Epub 2019 Jan 17.

Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline.

Author information

1
INSERM U1151, Institut Necker Enfants-Malades (INEM), Team 14, Université Paris Descartes-Sorbonne-Paris Cité, 75014 Paris, France.
2
INSERM U1151, Institut Necker Enfants-Malades (INEM), Team 1, Université Paris Descartes-Sorbonne-Paris Cité, 75014 Paris, France.
3
Grenoble Institut des Neurosciences, INSERM U1216, Equipe Neuropathologies et Dysfonctions Synaptiques, Université Grenoble Alpes, Grenoble, France.
4
Department of Biological Sciences, City University of New York-Hunter College, 695 Park Avenue, New York, NY 10065, USA.
5
Department of Cell Biology and Disease Mechanisms, Telethon Institute of Genetics and Medicine, Naples, Italy.
6
INSERM U1151, Institut Necker Enfants-Malades (INEM), Team 5, Université Paris Descartes-Sorbonne-Paris Cité, 75014 Paris, France.
7
INSERM U1151, Institut Necker Enfants-Malades (INEM), Team 1, Université Paris Descartes-Sorbonne-Paris Cité, 75014 Paris, France. Electronic address: patrice.codogno@inserm.fr.
8
INSERM U1151, Institut Necker Enfants-Malades (INEM), Team 14, Université Paris Descartes-Sorbonne-Paris Cité, 75014 Paris, France. Electronic address: franck.oury@inserm.fr.

Abstract

Age-related declines in cognitive fitness are associated with a reduction in autophagy, an intracellular lysosomal catabolic process that regulates protein homeostasis and organelle turnover. However, the functional significance of autophagy in regulating cognitive function and its decline during aging remains largely elusive. Here, we show that stimulating memory upregulates autophagy in the hippocampus. Using hippocampal injections of genetic and pharmacological modulators of autophagy, we find that inducing autophagy in hippocampal neurons is required to form novel memory by promoting activity-dependent structural and functional synaptic plasticity, including dendritic spine formation, neuronal facilitation, and long-term potentiation. We show that hippocampal autophagy activity is reduced during aging and that restoring its levels is sufficient to reverse age-related memory deficits. Moreover, we demonstrate that systemic administration of young plasma into aged mice rejuvenates memory in an autophagy-dependent manner, suggesting a prominent role for autophagy to favor the communication between systemic factors and neurons in fostering cognition. Among these youthful factors, we identify osteocalcin, a bone-derived molecule, as a direct hormonal inducer of hippocampal autophagy. Our results reveal that inducing autophagy in hippocampal neurons is a necessary mechanism to enhance the integration of novel stimulations of memory and to promote the influence of systemic factors on cognitive fitness. We also demonstrate the potential therapeutic benefits of modulating autophagy in the aged brain to counteract age-related cognitive impairments.

KEYWORDS:

aging; autophagy; beclin 1; hippocampus; memory formation; osteocalcin; synaptic plasticity; systemic milieu; youthful circulating factors

PMID:
30661803
DOI:
10.1016/j.cub.2018.12.021

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