Neuronal O-GlcNAcylation Improves Cognitive Function in the Aged Mouse Brain

Elizabeth G Wheatley; Eddy Albarran; Charles W White 3rd; Gregor Bieri; Cesar Sanchez-Diaz; Karishma Pratt; Cedric E Snethlage; Jun B Ding; Saul A Villeda

doi:10.1016/j.cub.2019.08.003

Neuronal O-GlcNAcylation Improves Cognitive Function in the Aged Mouse Brain

Curr Biol. 2019 Oct 21;29(20):3359-3369.e4. doi: 10.1016/j.cub.2019.08.003. Epub 2019 Oct 3.

Authors

Elizabeth G Wheatley¹, Eddy Albarran², Charles W White 3rd¹, Gregor Bieri³, Cesar Sanchez-Diaz³, Karishma Pratt¹, Cedric E Snethlage³, Jun B Ding², Saul A Villeda⁴

Affiliations

¹ Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
² Neuroscience IDP Program, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
³ Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, San Francisco, CA 94143, USA; The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, CA 94143, USA. Electronic address: saul.villeda@ucsf.edu.

Abstract

Mounting evidence in animal models indicates potential for rejuvenation of cellular and cognitive functions in the aging brain. However, the ability to utilize this potential is predicated on identifying molecular targets that reverse the effects of aging in vulnerable regions of the brain, such as the hippocampus. The dynamic post-translational modification O-linked N-Acetylglucosamine (O-GlcNAc) has emerged as an attractive target for regulating aging-specific synaptic alterations as well as neurodegeneration. While speculation exists about the role of O-GlcNAc in neurodegenerative conditions, such as Alzheimer's disease, its role in physiological brain aging remains largely unexplored. Here, we report that countering age-related decreased O-GlcNAc transferase (OGT) expression and O-GlcNAcylation ameliorates cognitive impairments in aged mice. Mimicking an aged condition in young adults by abrogating OGT, using a temporally controlled neuron-specific conditional knockout mouse model, recapitulated cellular and cognitive features of brain aging. Conversely, overexpressing OGT in mature hippocampal neurons using a viral-mediated approach enhanced associative fear memory in young adult mice. Excitingly, in aged mice overexpressing neuronal OGT in the aged hippocampus rescued in part age-related impairments in spatial learning and memory as well as associative fear memory. Our data identify O-GlcNAcylaton as a key molecular mediator promoting cognitive rejuvenation.

Keywords: O-GlcNAcylation; OGT; aging; brain; cognition; hippocampus; rejuvenation; synaptic plasticity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Acetylglucosamine / metabolism*
Acylation
Aging / physiology*
Animals
Cognition / physiology*
Male
Mice
Mice, Knockout
N-Acetylglucosaminyltransferases / metabolism*

Substances

N-Acetylglucosaminyltransferases
O-GlcNAc transferase
Acetylglucosamine

Abstract

Publication types

MeSH terms

Substances

Grants and funding