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2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer's resilience

Journal Article
Amit Kumar, Saravanan S Karuppagounder, Yingxin Chen, Carlo Corona, Riki Kawaguchi, Yuyan Cheng, Mustafa Balkaya, Botir T Sagdullaev, Zhexing Wen, Charles Stuart, Sunghee Cho, Guo-Li Ming, Jürgen Tuvikene, Tõnis Timmusk, Daniel H Geschwind, Rajiv R Ratan
Year Published: 
Neuron . 2023 Jul 11;S0896-6273(23)00472-5. doi: 10.1016/j.neuron.2023.06.013. Online ahead of print.
PMID: 37453419 | DOI: 10.1016/j.neuron.2023.06.013
Full Text on Neuron


Intermittent fasting (IF) is a diet with salutary effects on cognitive aging, Alzheimer's disease (AD), and stroke. IF restricts a number of nutrient components, including glucose. 2-deoxyglucose (2-DG), a glucose analog, can be used to mimic glucose restriction. 2-DG induced transcription of the pro-plasticity factor, Bdnf, in the brain without ketosis. Accordingly, 2-DG enhanced memory in an AD model (5xFAD) and functional recovery in an ischemic stroke model. 2-DG increased Bdnf transcription via reduced N-linked glycosylation, consequent ER stress, and activity of ATF4 at an enhancer of the Bdnf gene, as well as other regulatory regions of plasticity/regeneration (e.g., Creb5, Cdc42bpa, Ppp3cc, and Atf3) genes. These findings demonstrate an unrecognized role for N-linked glycosylation as an adaptive sensor to reduced glucose availability. They further demonstrate that ER stress induced by 2-DG can, in the absence of ketosis, lead to the transcription of genes involved in plasticity and cognitive resilience as well as proteostasis.


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