ArticleJournal of Alzheimer's disease : JAD2020
Glutamine Antagonist JHU-083 Normalizes Aberrant Hippocampal Glutaminase Activity and Improves Cognition in APOE4 Mice.
Article in Journal of Alzheimer's disease : JAD, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 26 citations in OpenAlex.
- CD11c + microglia: From basic research to clinical application.Neural regeneration research · 2026Article
- Recent insights into the roles and therapeutic potentials of GLS1 in inflammatory diseases.Journal of pharmaceutical analysis · 2025Review
- Inhibition of microglial glutaminase alleviates chronic stress-induced neurobehavioral and cognitive deficits.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- The multifaceted roles of apolipoprotein E4 in Alzheimer's disease pathology and potential therapeutic strategies.Cell death discovery · 2025Review
- Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research.Molecular neurodegeneration · 2025Review
- The Effect of glna Loss on the Physiological and Pathological Phenotype of Parkinson's Disease C. elegans.Journal of clinical laboratory analysis · 2024Article
- Unique tau- and synuclein-dependent metabolic reprogramming in neurons distinct from normal aging.Aging cell · 2024Article
- Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis.Nature communications · 2023Article
- Metabolic regulation of microglial phagocytosis: Implications for Alzheimer's disease therapeutics.Translational neurodegeneration · 2023Review
- T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade.JCI insight · 2023Article
- Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug.Science advances · 2022Article
- Mitochondrial dysfunction in microglia: a novel perspective for pathogenesis of Alzheimer's disease.Journal of neuroinflammation · 2022Review
- Microglia activation in the mPFC mediates anxiety-like behaviors caused by Staphylococcus aureus strain USA300.Brain and behavior · 2022Article
- P2X7 Receptor Augments LPS-Induced Nitrosative Stress by Regulating Nrf2 and GSH Levels in the Mouse Hippocampus.Antioxidants (Basel, Switzerland) · 2022Article
- Microglia in the Neuroinflammatory Pathogenesis of Alzheimer's Disease and Related Therapeutic Targets.Frontiers in immunology · 2022Review
- APC/C-Cdh1-targeted substrates as potential therapies for Alzheimer's disease.Frontiers in pharmacology · 2022Review
- Model studies towards prodrugs of the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) containing a diazo precursor.Bioorganic & medicinal chemistry letters · 2021Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundGiven the emergent aging population, the identification of effective treatments for Alzheimer's disease (AD) is critical.
objectiveWe investigated the therapeutic efficacy of JHU-083, a brain-penetrable glutamine antagonist, in treating AD using the humanized APOE4 knock-in mouse model.
methodsCell culture studies were performed using BV2 cells and primary microglia isolated from hippocampi of adult APOE4 knock-in mice to evaluate the effect of JHU-083 treatment on LPS-induced glutaminase (GLS) activity and inflammatory markers. Six-month-old APOE4 knock-in mice were administered JHU-083 or vehicle via oral gavage 3x/week for 4-5 months and cognitive performance was assessed using the Barnes maze. Target engagement in the brain was confirmed using a radiolabeled GLS enzymatic activity assay, and electrophysiology, gastrointestinal histology, blood chemistry, and CBC analyses were conducted to evaluate the tolerability of JHU-083.
resultsJHU-083 inhibited the LPS-mediated increases in GLS activity, nitic oxide release, and pro-inflammatory cytokine production in cultured BV2 cells and primary microglia isolated from APOE4 knock-in AD mice. Chronic treatment with JHU-083 in APOE4 mice improved hippocampal-dependent Barnes maze performance. Consistent with the cell culture findings,postmortem analyses of APOE4 mice showed increased GLS activity in hippocampal CD11b+ enriched cells versus age-matched controls, which was completely normalized by JHU-083 treatment. JHU-083 was well-tolerated, showing no weight loss effect or overt behavioral changes. Peripheral nerve function, gastrointestinal histopathology, and CBC/clinical chemistry parameters were all unaffected by chronic JHU-083 treatment.
conclusionThese results suggest that the attenuation of upregulated hippocampal glutaminase by JHU-083 represents a new therapeutic strategy for AD.
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