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

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. [Display omitted] • 2-deoxyglucose (2-DG), a glucose-restriction mimetic, drives Bdnf transcription • 2-DG reduces disability after ischemic stroke and improves cognition in AD • 2-DG inhibits N-glycosylation to induce ER stress, ATF4, and Bdnf transcription • N-glycosylation senses low glucose to drive adaptation to stroke and AD Intermittent fasting (IF) is a nutritional paradigm that forestalls cognitive aging, stroke disability, and Alzheimer's progression. How glucose restriction, an aspect of IF, contributes to IF-induced benefits is unclear. Here, we used 2-deoxyglucose to elucidate how low glucose engages an evolutionarily conserved ER stress response pathway to stimulate brain plasticity and treat stroke and AD. [ABSTRACT FROM AUTHOR]