Increasing O-GlcNAcylation is neuroprotective in young and aged brains after ischemic stroke.

dc.contributor.author

Wang, Zhuoran

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Li, Xuan

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Spasojevic, Ivan

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Lu, Liping

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Shen, Yuntian

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Qu, Xingguang

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Hoffmann, Ulrike

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Warner, David S

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Paschen, Wulf

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Sheng, Huaxin

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Yang, Wei

dc.date.accessioned

2021-06-01T13:24:49Z

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2021-06-01T13:24:49Z

dc.date.issued

2021-05

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2021-06-01T13:24:47Z

dc.description.abstract

Spliced X-box binding protein-1 (XBP1s) together with the hexosamine biosynthetic pathway (HBP) and O-GlcNAcylation forms the XBP1s/HBP/O-GlcNAc axis. Our previous studies have provided evidence that activation of this axis is neuroprotective after ischemic stroke and critically, ischemia-induced O-GlcNAcylation is impaired in the aged brain. However, the XBP1s' neuroprotective role and its link to O-GlcNAcylation in stroke, as well as the therapeutic potential of targeting this axis in stroke, have not been well established. Moreover, the mechanisms underlying this age-related impairment of O-GlcNAcylation induction after brain ischemia remain completely unknown. In this study, using transient ischemic stroke models, we first demonstrated that neuron-specific overexpression of Xbp1s improved outcome, and pharmacologically boosting O-GlcNAcylation with thiamet-G reversed worse outcome observed in neuron-specific Xbp1 knockout mice. We further showed that thiamet-G treatment improved long-term functional recovery in both young and aged animals after transient ischemic stroke. Mechanistically, using an analytic approach developed here, we discovered that availability of UDP-GlcNAc was compromised in the aged brain, which may constitute a novel mechanism responsible for the impaired O-GlcNAcylation activation in the aged brain after ischemia. Finally, based on this new mechanistic finding, we evaluated and confirmed the therapeutic effects of glucosamine treatment in young and aged animals using both transient and permanent stroke models. Our data together support that increasing O-GlcNAcylation is a promising strategy in stroke therapy.

dc.identifier

S0014-4886(21)00051-0

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0014-4886

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1090-2430

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https://hdl.handle.net/10161/23234

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eng

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Elsevier BV

dc.relation.ispartof

Experimental neurology

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10.1016/j.expneurol.2021.113646

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Aging

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Glucosamine

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Neuroprotection

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O-GlcNAc

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Thiamet-G

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UDP-GlcNAc

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UPR

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XBP1

dc.title

Increasing O-GlcNAcylation is neuroprotective in young and aged brains after ischemic stroke.

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Journal article

duke.contributor.orcid

Spasojevic, Ivan|0000-0001-9890-6246

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Sheng, Huaxin|0000-0002-4325-2940

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Yang, Wei|0000-0001-5719-4393

pubs.begin-page

113646

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School of Medicine

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Anesthesiology

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Duke

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Clinical Science Departments

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Anesthesiology, Neuroanesthesia

pubs.publication-status

Published

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339

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