Glutamine Antagonist JHU-083 Normalizes Aberrant Hippocampal Glutaminase Activity and Improves Cognition in APOE4 Mice.

Journal of Alzheimer's Disease : JAD
Kristen R HollingerBarbara S Slusher

Abstract

Given the emergent aging population, the identification of effective treatments for Alzheimer's disease (AD) is critical. We investigated the therapeutic efficacy of JHU-083, a brain-penetrable glutamine antagonist, in treating AD using the humanized APOE4 knock-in mouse model. Cell 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. JHU-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 w...Continue Reading

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Citations

Dec 6, 2020·Brain, Behavior, and Immunity·Lu DingJialin C Zheng
May 8, 2021·Natural Product Research·Atsumi ShimadaMasanori Inagaki
Aug 18, 2021·Bioorganic & Medicinal Chemistry Letters·Run-Duo GaoTakashi Tsukamoto

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