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

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

doi:10.1016/j.neuron.2023.06.013

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

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

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	2831-2846.e10
Journal	Neuron
Volume	111
Issue number	18
DOIs	https://doi.org/10.1016/j.neuron.2023.06.013
State	Published - 20 Sep 2023
Externally published	Yes

Keywords

2-deoxyglucose
Alzheimer's disease
N-linked glycosylation
activating transcription factor 4
brain-derived neurotrophic factor
cognitive function
endoplasmic reticulum stress
intermittent fasting
ischemic stroke
learning and memory

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Kumar, A., Karuppagounder, S. S., Chen, Y., Corona, C., Kawaguchi, R., Cheng, Y., Balkaya, M., Sagdullaev, B. T., Wen, Z., Stuart, C., Cho, S., Ming, G. L., Tuvikene, J., Timmusk, T., Geschwind, D. H., & Ratan, R. R. (2023). 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer's resilience. Neuron, 111(18), 2831-2846.e10. https://doi.org/10.1016/j.neuron.2023.06.013

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

abstract = "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.",

keywords = "2-deoxyglucose, Alzheimer's disease, N-linked glycosylation, activating transcription factor 4, brain-derived neurotrophic factor, cognitive function, endoplasmic reticulum stress, intermittent fasting, ischemic stroke, learning and memory",

author = "Amit Kumar and Karuppagounder, \{Saravanan S.\} and Yingxin Chen and Carlo Corona and Riki Kawaguchi and Yuyan Cheng and Mustafa Balkaya and Sagdullaev, \{Botir T.\} and Zhexing Wen and Charles Stuart and Sunghee Cho and Ming, \{Guo li\} and J{\"u}rgen Tuvikene and T{\~o}nis Timmusk and Geschwind, \{Daniel H.\} and Ratan, \{Rajiv R.\}",

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year = "2023",

month = sep,

day = "20",

doi = "10.1016/j.neuron.2023.06.013",

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Kumar, A, Karuppagounder, SS, Chen, Y, Corona, C, Kawaguchi, R, Cheng, Y, Balkaya, M, Sagdullaev, BT, Wen, Z, Stuart, C, Cho, S, Ming, GL, Tuvikene, J, Timmusk, T, Geschwind, DH & Ratan, RR 2023, '2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer's resilience', Neuron, vol. 111, no. 18, pp. 2831-2846.e10. https://doi.org/10.1016/j.neuron.2023.06.013

TY - JOUR

T1 - 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer's resilience

AU - Kumar, Amit

AU - Karuppagounder, Saravanan S.

AU - Chen, Yingxin

AU - Corona, Carlo

AU - Kawaguchi, Riki

AU - Cheng, Yuyan

AU - Balkaya, Mustafa

AU - Sagdullaev, Botir T.

AU - Wen, Zhexing

AU - Stuart, Charles

AU - Cho, Sunghee

AU - Ming, Guo li

AU - Tuvikene, Jürgen

AU - Timmusk, Tõnis

AU - Geschwind, Daniel H.

AU - Ratan, Rajiv R.

PY - 2023/9/20

Y1 - 2023/9/20

N2 - 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.

AB - 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.

KW - 2-deoxyglucose

KW - Alzheimer's disease

KW - N-linked glycosylation

KW - activating transcription factor 4

KW - brain-derived neurotrophic factor

KW - cognitive function

KW - endoplasmic reticulum stress

KW - intermittent fasting

KW - ischemic stroke

KW - learning and memory

UR - https://www.scopus.com/pages/publications/85170088005

U2 - 10.1016/j.neuron.2023.06.013

DO - 10.1016/j.neuron.2023.06.013

M3 - Article

C2 - 37453419

AN - SCOPUS:85170088005

SN - 0896-6273

VL - 111

SP - 2831-2846.e10

JO - Neuron

JF - Neuron

IS - 18

ER -

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

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Keywords

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