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Amyloid in Mouse Microglia Cells1
,
,
* Department of Biomedical Sciences, Section of Pharmacology, University of Chieti, Chieti, Italy;
Department of Experimental Medicine, University of L’Aquila, L’Aquila, Italy;
Department of Oncology and Neuroscience, University of Chieti, Chieti, Italy;
Centre of Excellence on Aging, "G. D’Annunzio" Foundation, University of Chieti, Chieti, Italy; and
¶ Department of Medicine, Division of Neurology, and
|| Department of Surgery, McMaster University Health Sciences Centre, McMaster University, Hamilton, Ontario, Canada
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-
(10 ng/ml) plus TNF-
(50 ng/ml) or 
amyloid (A) peptide (A1–42; 500 nM). Culture pretreatment with guanosine (10–300 µM), starting 1 h before cytokine or A addition, dose-dependently inhibited the CD40-induced expression as well as functional CD40 signaling by suppressing IL-6 production promoted by IFN-/TNF- challenge in the presence of CD40 cross-linking. Moreover, guanosine abrogated IFN--induced phosphorylation on Ser727 and translocation of STAT-1 to the nucleus as well as TNF--/A-induced I
B and NF-B p65/RelA subunit phosphorylation, thus inhibiting NF-B-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-/TNF--induced CD40 expression and function as well as on STAT-1 or NF-B 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by funds to R.C. and F.C. from the Centre of Excellence on Aging of the University of Chieti and from the Italian Ministry of Education, University and Research.
2 Address correspondence and reprint requests to Dr. Renata Ciccarelli, Section of Pharmacology, Department of Biomedical Sciences, Medical School, University of Chieti, Via dei Vestini 29, pal. B. 66013 Chieti, Italy. E-mail address: r.ciccarelli{at}dsb.unich.it
3 Abbreviations used in this paper: A, amyloid; PTX, pertussis toxin; DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; ZM241385, 4-(2-[7-amino)]-2-(2-furyl(1,2,4)- triazolo(2,3-a(1,3,5)triazin-5-yl-amino ethyl)phenol); LY294002, [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydro chloride]; SB203580, [4-(4-fluorophenyl)-2-(4-methylsulfinyl phenyl)-5-(4-pyridyl)1H-imidazole]; U0126, [1,4-diamino-2, 3-dicyano-1,4-bis(2-quino phenylthio) butadiene]; PKB, protein kinase B; GAS, IFN- activation sequence.
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