Cited by 111Glycosylation and Glycoproteins ResearchMemory and Neural MechanismsNeurogenesis and neuroplasticity mechanisms

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

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Wheatley, Elizabeth G., Albarran, Eddy, White, Charles W., Bieri, Gregor, Sanchez-Diaz, Cesar, Pratt, Karishma, Snethlage, Cedric E., Ding, Jun B. +1 more·2019·Current Biology

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.

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Crossref · 10.1016/j.cub.2019.08.003

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  • STAT3, a transcription factor activated by inflammatory cytokines, is at least in part responsible for NSC differentiation being biased towards glial cells (rather than neurons) during ageing.

    “STAT3 — a transcription factor activated by inflammatory cytokines — is at least in part responsible for NSC differentiation being biased towards glial cells (rather than neurons) during ageing46,94.”

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Authors
Wheatley, E. G., Albarran, E., White, C. W., Bieri, G., Sanchez-Diaz, C., Pratt, K., Snethlage, C. E., Ding, J. B., & Villeda, S. A.
Affiliations
  • University of California, San Francisco (US)
  • Stanford Medicine (US)
Corresponding author
Villeda, Saul A.
Venue
Current Biology
Publisher
Elsevier BV
Published
2019-10
Volume
29
Issue
20
Pages
3359-3369.e4
ISSN
0960-9822 (ISSN-L)
OpenAlex
W2977249793
Cited by
107
References
41
Citations by year
2026: 12 · 2025: 13 · 2024: 16 · 2023: 25 · 2022: 17 · 2021: 14 · 2020: 9 · 2013: 1
FWCI
3.31
Type
journal article
Language
en
Open access
Locations
  • Current Biology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institute on Aging
  • National Institute of Neurological Disorders and Stroke
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
O-GlcNAcylation, O-GlcNAc transferase, brain aging, cognitive aging, hippocampal neurons, spatial learning and memory, conditional knockout mice, viral overexpression, neurodegeneration
MeSH terms
Acetylglucosamine, Acylation, Aging, Animals, Cognition, Male, N-Acetylglucosaminyltransferases, Mice, Knockout, Mice

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