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

Kumar, Amit; Karuppagounder, Saravanan S.; Chen, Yingxin; Corona, Carlo; Kawaguchi, Riki; Cheng, Yuyan; Balkaya, Mustafa; Sagdullaev, Botir T.; Wen, Zhexing; Stuart, Charles Alexander; Cho, Sunghee; Ming, Guo‐li; Tuvikene, Jürgen; Timmusk, Tõnis; Geschwind, Daniel H.; Ratan, Rajiv R.

doi:10.1016/j.neuron.2023.06.013

Cited by 16 publications

(3 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3b-c), consistent with 2DG reversing CCI-induced transcriptional changes. eIF2/eIF4 signaling and mTOR pathways were enriched in 2DG-associated GSEA after CCI, consistent with known 2DG effects following stroke 36 .…”

Section: Resultssupporting

confidence: 75%

“…The ketogenic diet, which shifts the brain from reliance on glycolysis to ketosis 74 , has a long history as an anticonvulsant and neuroprotective therapy 75 , and provided the rationale to use 2DG to inhibit glycolysis after injury 76 . 2DG is known to acutely reduce neuronal activity 77,78 , activate the NRSF pathway via changes in NADH/CtBP 79 , promote the adaptive ER stress-ATF4 pathway 36 , and enhance BDNF expression 77 . Our data supports that 2DG enhances oxidative metabolism, particularly in GABA-INs, in parallel to its other effects.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cortical inhibitory parvalbumin interneurons exhibit metabolic specializations coordinated by PGC-1α that are lost in rodents and humans after traumatic brain injury

Quiñones,

Wang,

Kim

et al. 2024

Preprint

View full text Add to dashboard Cite

Parvalbumin-positive interneurons (PV-INs) regulate neuronal and circuit activity, and their dysfunction is observed across neurological conditions, including traumatic brain injury (TBI), epilepsy, Alzheimer’s disease, and schizophrenia. PV-INs are particularly vulnerable to cell loss, potentially due to their increased metabolic demands arising from their uniquely high level of electrical activity, which render them susceptible to metabolic pressure. Here, we use single-nucleus RNA-sequencing (snRNAseq) data from a rodent model of TBI, as well as human TBI data, and demonstrate PV-INs have unique metabolic specializations that are lost after injury and can be rescued byin vivotreatment with the glycolytic inhibitor, 2-deoxyglucose. We generated a novel PV-IN transcriptional identity module comprised primarily of genes encoding specialized ion channels, metabolic enzymes, and synaptic machinery, that identifies heterogenous subsets of injury-associated PV-INs with loss of PV-IN transcriptional identity. We show that changes in metabolic specialization are coupled to changes in transcriptional identity in PV-INs and implicate the PV-IN-enriched transcriptional co-activator,Ppargc1a, as a key driver of PV-IN transcriptional metabolic dysfunction. We also identify a family of long non-coding RNAs enriched in this subset of transcriptionally dysfunctional PV-INs that negatively correlates with PV-IN metabolic specialization. Lastly, we utilize these tools to interrogate a published human TBI snRNAseq data set and find nearly identical changes, underscoring the importance of PV-IN metabolic dysfunction in the pathology of TBI.

show abstract

Section: Resultssupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Cortical inhibitory parvalbumin interneurons exhibit metabolic specializations coordinated by PGC-1α that are lost in rodents and humans after traumatic brain injury

Quiñones,

Wang,

Kim

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…During days 9-14, the Morris water maze test was performed for cognitive function measurement [38]. The MWM system mainly consisted of a black circular pool, a circular hidden platform which was submerged 1 cm below the water surface, and a video analysis system.…”

Section: Morris Water Maze (Mwm)mentioning

confidence: 99%

Hydrocortisone Mitigates Alzheimer’s-Related Cognitive Decline through Modulating Oxidative Stress and Neuroinflammation

Li,

Chen,

Liu

et al. 2023

Cells

View full text Add to dashboard Cite

Alzheimer’s disease (AD), an age-related degenerative disorder, is characterized by β-amyloid deposition, abnormal phosphorylation of tau proteins, synaptic dysfunction, neuroinflammation, and oxidative stress. Despite extensive research, there are no medications or therapeutic interventions to completely treat and reverse AD. Herein, we explore the potential of hydrocortisone (HC), a natural and endogenous glucocorticoid known to have potent anti-inflammatory properties, in an Aβ1–42-induced AD mouse model. Our investigation highlights the beneficial effects of HC administration on cognitive impairment, synaptic function enhancement, and neuronal protection in Aβ1–42-induced AD mice. Notably, HC treatment effectively suppresses the hyperactivation of microglia and astrocytes, leading to a reduction in proinflammatory factors and alleviation of neuroinflammation. Furthermore, HC intervention demonstrates the capacity to mitigate the generation of ROS and oxidative stress. These compelling findings underscore the potential therapeutic application of HC in AD and present promising opportunities for its utilization in AD prevention and treatment. The implications drawn from our findings indicate that hydrocortisone holds promise as a viable candidate for adjunctive use with other anti-AD drugs for the clinical management of patients presenting with moderate to severe AD.

show abstract

The catabolic - anabolic cycling hormesis model of health and resilience

Calabrese,

Mattson

2024

Ageing Research Reviews

View full text Add to dashboard Cite

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

Cited by 16 publications

References 86 publications

Cortical inhibitory parvalbumin interneurons exhibit metabolic specializations coordinated by PGC-1α that are lost in rodents and humans after traumatic brain injury

Cortical inhibitory parvalbumin interneurons exhibit metabolic specializations coordinated by PGC-1α that are lost in rodents and humans after traumatic brain injury

Hydrocortisone Mitigates Alzheimer’s-Related Cognitive Decline through Modulating Oxidative Stress and Neuroinflammation

The catabolic - anabolic cycling hormesis model of health and resilience

Contact Info

Product

Resources

About