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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: 
Science Direct 14 July 2023
Full Text on Science Direct


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., Creb5Cdc42bpaPpp3cc, 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.