The Intermittent Fasting Mimetic, 2-deoxyglucose, Reprograms Brain Derived Neurotrophic Factor (BDNF) transcription via an Adaptive ER Stress-ATF4 Pathway and Improves Outcomes in Alzheimer’s and Stroke Models [ChIP-seq]

ABSTRACT: Intermittent fasting (IF) has broad beneficial effects on brain pathophysiology. Here, we sought to identify the target required for beneficial effects of IF using its pharmacological mimic, 2-deoxyglucose (2-DG), which could also eliminate limitations of human IF application due to dosage and schedule issues. 2-DG transcriptionally induced plasticity gene, Bdnf in vitro and in vivo. A 2-DG dose that induced Bdnf transcription in vivo also normalized hippocampal long-term potentiation and memory in an AD mouse model (5xFAD) and significantly improved functional recovery in stroke models. 2-DG enhanced Bdnf transcription by decreasing N-linked glycosylation that induced ER stress and the activity of newly translated ATF4 at +3kb intronic enhancer region of Bdnf gene. These data highlight the critical role of N-linked glycosylation in glucose sensing and suggest that 2-DG can improve outcomes without inducing ketosis via an adaptive ER stress pathway culminating in the transcription of CNS-associated resilience genes including Bdnf. n our preliminary in-vitro studies in primary neurons, we found that changing glucose utlization using 2-deoxyglucose (2-DG, a known glycolytic inhibitor, which inhibits glucose utilization) led to a dose dependent signficant increase in Bdnf gene expression. Additionally, the dose of 2-DG that induced Bdnf gene expression also normalized learning and memory in mouse model of AD (5xFAD mouse) and improved functional recovery in mice models of ischemic and hemorrhagic strokes. With RNA Sequencing of 2-DG treated primary neuronal samples, our first goal was to identify dominant gene signatures in response to 2-deoxyglucose in order to delineate critical pathways affected by changes in glucose metabolism and our second goal was to understand if 2-deoxyglucose affect a broad gene plasticity program or only a few selective plasticity genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE217282 | GEO | 2023/11/28

REPOSITORIES: GEO