Related Experiment Video
Updated: Jul 17, 2026
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Guanosine inhibits CD40 receptor expression and function induced by cytokines and beta amyloid in mouse microglia
Iolanda D'Alimonte1, Vincenzo Flati, Mariagrazia D'Auro
1Department of Biomedical Sciences, Section of Pharmacology, University of Chieti, Via dei Vestini 29, 66013 Chieti, Italy.
Abstract:
Growing evidence implicates CD40, a member of the TNFR superfamily, as contributing to the pathogenesis of many neurodegenerative diseases. Thus, strategies to suppress its expression may be of benefit in those disorders. To this aim, we investigated the effect of guanosine, a purine nucleoside that exerts neurotrophic and neuroprotective effects. CD40 expression and function are increased by exposure of mouse microglia cultures or the N9 microglia cell line to IFN-gamma (10 ng/ml) plus TNF-alpha (50 ng/ml) or beta amyloid (Abeta) peptide (Abeta(1-42); 500 nM). Culture pretreatment with guanosine (10-300 microM), starting 1 h before cytokine or Abeta addition, dose-dependently inhibited the CD40-induced expression as well as functional CD40 signaling by suppressing IL-6 production promoted by IFN-gamma/TNF-alpha challenge in the presence of CD40 cross-linking. Moreover, guanosine abrogated IFN-gamma-induced phosphorylation on Ser(727) and translocation of STAT-1alpha to the nucleus as well as TNF-alpha-/Abeta-induced IkappaBalpha and NF-kappaB p65/RelA subunit phosphorylation, thus inhibiting NF-kappaB-induced nuclear translocation. Guanosine effects were mediated by an increased phosphorylation of Akt, a PI3K downstream effector, as well as of ERK1/2 and p38 in the MAPK system, because culture pretreatment with selective ERK1/2, p38 MAPK, and PI3K antagonists (U0126, SB203580, or LY294002, respectively) counteracted guanosine inhibition on IFN-gamma/TNF-alpha-induced CD40 expression and function as well as on STAT-1alpha or NF-kappaB nuclear translocation. These findings suggest a role for guanosine as a potential drug in the experimental therapy of neuroinflammatory/neurodegenerative diseases, particularly Alzheimer's disease.
Insights
Guanoine, a neuroprotective compound, inhibits CD40 expression and signaling in microglia, offering potential therapeutic benefits for neurodegenerative diseases like Alzheimer's.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- CD40, a TNFR superfamily member, contributes to neurodegenerative disease pathogenesis.
- Suppressing CD40 expression may offer therapeutic benefits for these disorders.
Purpose of the Study:
- To investigate the effect of guanosine on CD40 expression and function in microglia.
- To explore guanosine's potential as a therapeutic agent for neuroinflammatory/neurodegenerative diseases.
Main Methods:
- Mouse microglia and N9 cell line exposed to IFN-gamma, TNF-alpha, or beta-amyloid peptide.
- Pretreatment with guanosine to assess its impact on CD40 expression, IL-6 production, and signaling pathways (STAT-1alpha, NF-kappaB).
- Utilized PI3K and MAPK pathway antagonists to elucidate guanosine's mechanism of action.
Main Results:
- Guanoine dose-dependently inhibited CD40-induced expression and IL-6 production.
- Guanoine suppressed STAT-1alpha and NF-kappaB nuclear translocation.
- Guanoine's effects were mediated by increased Akt, ERK1/2, and p38 phosphorylation, confirmed by antagonist studies.
Conclusions:
- Guanoine effectively inhibits CD40-mediated inflammatory signaling in microglia.
- Guanoine demonstrates potential as a therapeutic agent for neuroinflammatory and neurodegenerative conditions, including Alzheimer's disease.
Related Concept Videos
01:19Inhibitors of Virion Maturation and Assembly
01:30Inhibitors of Viral Protein Synthesis