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

• Published in: Current biology Vol. 29; no. 20; pp. 3359 - 3369.e4
• Main Authors: Wheatley, Elizabeth G., Albarran, Eddy, White, Charles W., Bieri, Gregor, Sanchez-Diaz, Cesar, Pratt, Karishma, Snethlage, Cedric E., Ding, Jun B., Villeda, Saul A.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 21.10.2019
• Subjects: Acetylglucosamine - metabolism; Acylation; aging; Aging - physiology; Animals; brain; cognition; Cognition - physiology; hippocampus; Male; Mice; Mice, Knockout; N-Acetylglucosaminyltransferases - metabolism; O-GlcNAcylation; OGT; rejuvenation; synaptic plasticity; cognition; hippocampus; O-GlcNAcylation; aging; synaptic plasticity; rejuvenation; brain; OGT
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2019.08.003

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. [Display omitted] •Decreased hippocampal OGT and O-GlcNAcylation accompany neuronal hallmarks of aging•Decreasing neuronal OGT in the young hippocampus impairs plasticity and cognition•Increasing neuronal OGT in the young hippocampus enhances cognition•Restoring neuronal OGT in the aged hippocampus rescues cognitive impairments Wheatley et al. identify O-GlcNAcylation as a key posttranslational modification promoting cognitive rejuvenation. Mimicking age-related decreased neuronal OGT and O-GlcNAc levels in the young hippocampus impaired cognition, while restoring neuronal OGT and O-GlcNAc in the aged hippocampus rejuvenated cognition.