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CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid.
Neuroscience. 2015 Aug 27; 302:112-20.N

Abstract

Activation of microglia associated with neuroinflammation and loss of phagocytic activity is considered to play a prominent role in the pathogenesis of Alzheimer's disease (AD). CHF5074 (CSP-1103) has been shown to improve cognition and reduce brain inflammation in patients with mild cognitive impairment (MCI). CHF5074 was also found to reverse impairments in recognition memory and improve hippocampal long-term potentiation when administered to plaque-free Tg2576 mice (5-month-old) for 4 weeks. Though, no investigation has focused on the consequence of CHF5074 treatment on microglia polarization yet. In this study we evaluated the effect of CHF5074 administration (375 ppm in the diet) to 5-month-old Tg2576 mice on the expression of pro-inflammatory (M1) genes, Interleukin 1 beta (IL-1β), Tumor Necrosis Factor alpha (TNFα) and inducible Nitric Oxide Synthase (iNOS), and anti-inflammatory/phagocytic (M2) markers Mannose Receptor type C 1 (MRC1/CD206), Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Chitinase 3-like 3 (Ym1). No changes of pro-inflammatory gene transcription but a reduced expression of MRC1/CD206, TREM2 and Ym1 were detected in the hippocampus of young Tg2576 mice receiving normal diet, when compared to wild-type littermates. CHF5074 did not affect the pro-inflammatory transcription but significantly increased the expression of MRC1/CD206 and Ym1. CHF5074 effects appeared to be hippocampus-specific, as the M2 transcripts were only slightly modified in the cerebral cortex. In primary cultures of mouse astrocyte-microglia, CHF5074 totally suppressed the expression of TNF-α, IL-1β and iNOS induced by 10 μM β-amyloid1-42 (Aβ42). Moreover, CHF5074 significantly increased the expression of anti-inflammatory/phagocytic markers MRC1/CD206 and TREM2, reduced by the Aβ42 application alone. The effect of CHF5074 was not reproduced by ibuprofen (3 μM or 500 μM) or R-flurbiprofen (3 μM or 100 μM), as both compounds limited the pro-inflammatory gene expression but did not modify the anti-inflammatory/phagocytic transcription. These data show that CHF5074 specifically drives the expression of microglia M2 markers either in young Tg2576 hippocampus or in primary astrocyte-microglia cultures, suggesting its potential therapeutic efficacy as microglial modulator in the early phase of AD.

Authors+Show Affiliations

Department of Molecular and Translational Medicine, University of Brescia and National Institute of Neuroscience, Viale Europa 11, 25123 Brescia, Italy; IRCCS San Camillo Hospital, Via Alberoni 70, 30126 Venice, Italy.Department of Molecular and Translational Medicine, University of Brescia and National Institute of Neuroscience, Viale Europa 11, 25123 Brescia, Italy.Department of Molecular and Translational Medicine, University of Brescia and National Institute of Neuroscience, Viale Europa 11, 25123 Brescia, Italy.Department of Molecular and Translational Medicine, University of Brescia and National Institute of Neuroscience, Viale Europa 11, 25123 Brescia, Italy.Department of Molecular and Translational Medicine, University of Brescia and National Institute of Neuroscience, Viale Europa 11, 25123 Brescia, Italy.Health Science and Technologies, Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Via Tolara di Sopra 41/E, 40064 Ozzano Emilia, Bologna, Italy.Health Science and Technologies, Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Via Tolara di Sopra 41/E, 40064 Ozzano Emilia, Bologna, Italy; Department of Pharmacy and Biotechnology, University of Bologna, Via Tolara di Sopra 41/E, 40064 Ozzano Emilia, Bologna, Italy; IRET Foundation, Via Tolara di Sopra 41/E, 40064 Ozzano Emilia, Bologna, Italy.IRCCS San Camillo Hospital, Via Alberoni 70, 30126 Venice, Italy.Department of Molecular and Translational Medicine, University of Brescia and National Institute of Neuroscience, Viale Europa 11, 25123 Brescia, Italy; IRCCS San Camillo Hospital, Via Alberoni 70, 30126 Venice, Italy.Research & Development, Chiesi Farmaceutici, Via Palermo 26/A, 43100 Parma, Italy.Department of Molecular and Translational Medicine, University of Brescia and National Institute of Neuroscience, Viale Europa 11, 25123 Brescia, Italy; IRCCS San Camillo Hospital, Via Alberoni 70, 30126 Venice, Italy. Electronic address: marina.pizzi@unibs.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25450955

Citation

Porrini, V, et al. "CHF5074 (CSP-1103) Induces Microglia Alternative Activation in Plaque-free Tg2576 Mice and Primary Glial Cultures Exposed to Beta-amyloid." Neuroscience, vol. 302, 2015, pp. 112-20.
Porrini V, Lanzillotta A, Branca C, et al. CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid. Neuroscience. 2015;302:112-20.
Porrini, V., Lanzillotta, A., Branca, C., Benarese, M., Parrella, E., Lorenzini, L., Calzà, L., Flaibani, R., Spano, P. F., Imbimbo, B. P., & Pizzi, M. (2015). CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid. Neuroscience, 302, 112-20. https://doi.org/10.1016/j.neuroscience.2014.10.029
Porrini V, et al. CHF5074 (CSP-1103) Induces Microglia Alternative Activation in Plaque-free Tg2576 Mice and Primary Glial Cultures Exposed to Beta-amyloid. Neuroscience. 2015 Aug 27;302:112-20. PubMed PMID: 25450955.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid. AU - Porrini,V, AU - Lanzillotta,A, AU - Branca,C, AU - Benarese,M, AU - Parrella,E, AU - Lorenzini,L, AU - Calzà,L, AU - Flaibani,R, AU - Spano,P F, AU - Imbimbo,B P, AU - Pizzi,M, Y1 - 2014/10/22/ PY - 2014/07/30/received PY - 2014/10/06/revised PY - 2014/10/13/accepted PY - 2014/12/3/entrez PY - 2014/12/3/pubmed PY - 2016/4/27/medline KW - Alzheimer’s disease KW - CHF5074 KW - CSP-1103 KW - Microglia KW - Neuroinflammation KW - Tg2576 SP - 112 EP - 20 JF - Neuroscience JO - Neuroscience VL - 302 N2 - Activation of microglia associated with neuroinflammation and loss of phagocytic activity is considered to play a prominent role in the pathogenesis of Alzheimer's disease (AD). CHF5074 (CSP-1103) has been shown to improve cognition and reduce brain inflammation in patients with mild cognitive impairment (MCI). CHF5074 was also found to reverse impairments in recognition memory and improve hippocampal long-term potentiation when administered to plaque-free Tg2576 mice (5-month-old) for 4 weeks. Though, no investigation has focused on the consequence of CHF5074 treatment on microglia polarization yet. In this study we evaluated the effect of CHF5074 administration (375 ppm in the diet) to 5-month-old Tg2576 mice on the expression of pro-inflammatory (M1) genes, Interleukin 1 beta (IL-1β), Tumor Necrosis Factor alpha (TNFα) and inducible Nitric Oxide Synthase (iNOS), and anti-inflammatory/phagocytic (M2) markers Mannose Receptor type C 1 (MRC1/CD206), Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Chitinase 3-like 3 (Ym1). No changes of pro-inflammatory gene transcription but a reduced expression of MRC1/CD206, TREM2 and Ym1 were detected in the hippocampus of young Tg2576 mice receiving normal diet, when compared to wild-type littermates. CHF5074 did not affect the pro-inflammatory transcription but significantly increased the expression of MRC1/CD206 and Ym1. CHF5074 effects appeared to be hippocampus-specific, as the M2 transcripts were only slightly modified in the cerebral cortex. In primary cultures of mouse astrocyte-microglia, CHF5074 totally suppressed the expression of TNF-α, IL-1β and iNOS induced by 10 μM β-amyloid1-42 (Aβ42). Moreover, CHF5074 significantly increased the expression of anti-inflammatory/phagocytic markers MRC1/CD206 and TREM2, reduced by the Aβ42 application alone. The effect of CHF5074 was not reproduced by ibuprofen (3 μM or 500 μM) or R-flurbiprofen (3 μM or 100 μM), as both compounds limited the pro-inflammatory gene expression but did not modify the anti-inflammatory/phagocytic transcription. These data show that CHF5074 specifically drives the expression of microglia M2 markers either in young Tg2576 hippocampus or in primary astrocyte-microglia cultures, suggesting its potential therapeutic efficacy as microglial modulator in the early phase of AD. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/25450955/CHF5074__CSP_1103__induces_microglia_alternative_activation_in_plaque_free_Tg2576_mice_and_primary_glial_cultures_exposed_to_beta_amyloid_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(14)00893-8 DB - PRIME DP - Unbound Medicine ER -