ArticleJournal of neuroinflammation2016
The mixed-lineage kinase 3 inhibitor URMC-099 facilitates microglial amyloid-β degradation.
Article in Journal of neuroinflammation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- Article
- Hippocampal GPR35 Participates in the Pathogenesis of Cognitive Deficits and Emotional Alterations Induced by AβMolecular neurobiology · 2025Article
- Hybrid Amyloid Quantum Dot Nano-Bio Assemblies to Probe Neuroinflammatory Damage.ACS chemical neuroscience · 2024Article
- Infectious Diseases.Advances in neurobiology · 2024Review
- URMC-099 prophylaxis prevents hippocampal vascular vulnerability and synaptic damage in an orthopedic model of delirium superimposed on dementia.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Europium-Doped Cerium Oxide Nanoparticles for Microglial Amyloid Beta Clearance and Homeostasis.ACS chemical neuroscience · 2022Article
- c-JUN n-Terminal Kinase (JNK) Signaling in Autosomal Dominant Polycystic Kidney Disease.Journal of cellular signaling · 2022Article
- c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease.PLoS genetics · 2021Article
- The regulatory function of mixed lineage kinase 3 in tumor and host immunity.Pharmacology & therapeutics · 2021Review
- Selection of viral variants during persistent infection of insectivorous bat cells with Middle East respiratory syndrome coronavirus.Scientific reports · 2020Article
- The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders.Journal of neuroinflammation · 2019Article
- The second generation mixed lineage kinase-3 (MLK3) inhibitor CLFB-1134 protects against neurotoxin-induced nigral dopaminergic neuron loss.Experimental neurology · 2019Article
- URMC-099 facilitates amyloid-β clearance in a murine model of Alzheimer's disease.Journal of neuroinflammation · 2018Article
- Anti-retroviral drugs: current state and development in the next decade.Acta pharmaceutica Sinica. B · 2018Review
- Mixed Lineage Kinase 3 Mediates the Induction of CXCL10 by a STAT1-Dependent Mechanism During Hepatocyte Lipotoxicity.Journal of cellular biochemistry · 2017Article
- Mixed-lineage kinase 3 pharmacological inhibition attenuates murine nonalcoholic steatohepatitis.JCI insight · 2017Article
- Amelioration of amyloid-β-induced deficits by DcR3 in an Alzheimer's disease model.Molecular neurodegeneration · 2017Article
- Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs.The Journal of clinical investigation · 2017Article
- Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundAmyloid-β (Aβ)-stimulated microglial inflammatory responses engage mitogen-activated protein kinase (MAPK) pathways in Alzheimer's disease (AD). Mixed-lineage kinases (MLKs) regulate upstream MAPK signaling that include p38 MAPK and c-Jun amino-terminal kinase (JNK). However, whether MLK-MAPK pathways affect Aβ-mediated neuroinflammation is unknown. To this end, we investigated if URMC-099, a brain-penetrant small-molecule MLK type 3 inhibitor, can modulate Aβ trafficking and processing required for generating AD-associated microglial inflammatory responses.
methodsAβ1-42 (Aβ42) and/or URMC-099-treated murine microglia were investigated for phosphorylated mitogen-activated protein kinase kinase (MKK)3, MKK4 (p-MKK3, p-MKK4), p38 (p-p38), and JNK (p-JNK). These pathways were studied in tandem with the expression of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Gene expression of the anti-inflammatory cytokines, IL-4 and IL-13, was evaluated by real-time quantitative polymerase chain reaction. Aβ uptake and expression of scavenger receptors were measured. Protein trafficking was assessed by measures of endolysosomal markers using confocal microscopy.
resultsAβ42-mediated microglial activation pathways were shown by phosphorylation of MKK3, MKK4, p38, and JNK and by expression of IL-1β, IL-6, and TNF-α. URMC-099 modulated microglial inflammatory responses with induction of IL-4 and IL-13. Phagocytosis of Aβ42 was facilitated by URMC-099 with up-regulation of scavenger receptors. Co-localization of Aβ and endolysosomal markers associated with enhanced Aβ42 degradation was observed.
conclusionsURMC-099 reduced microglial inflammatory responses and facilitated phagolysosomal trafficking with associated Aβ degradation. These data demonstrate a new immunomodulatory role for URMC-099 to inhibit MLK and to induce microglial anti-inflammatory responses. Thus, URMC-099 may be developed further as a novel disease-modifying AD therapy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.