Overexpression of SIRT1 protein in neurons protects against experimental autoimmune encephalomyelitis through activation of multiple SIRT1 targets

Treatment of experimental autoimmune encephalomyelitis (EAE) with resveratrol, an activator of sirtuin 1 (SIRT1), reduces disease severity. This suggested that activators of SIRT1, a highly conserved NAD-dependent protein deacetylase, might have immune-modulating or neuroprotective therapeutic effec...

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Published in:	The Journal of immunology (1950) Vol. 190; no. 9; pp. 4595 - 4607
Main Authors:	Nimmagadda, Vamshi K, Bever, Christopher T, Vattikunta, Narasimha R, Talat, Saifi, Ahmad, Vakas, Nagalla, Naveen K, Trisler, David, Judge, Susan I V, Royal, 3rd, Walter, Chandrasekaran, Krish, Russell, James W, Makar, Tapas K
Format:	Journal Article
Language:	English
Published:	United States 01-05-2013
Subjects:	Animals Apoptosis - drug effects Apoptosis - immunology Axons - drug effects Axons - immunology Axons - metabolism Brain-Derived Neurotrophic Factor - immunology Brain-Derived Neurotrophic Factor - metabolism Demyelinating Diseases - drug therapy Demyelinating Diseases - immunology Demyelinating Diseases - metabolism Encephalomyelitis, Autoimmune, Experimental - drug therapy Encephalomyelitis, Autoimmune, Experimental - immunology Encephalomyelitis, Autoimmune, Experimental - metabolism Encephalomyelitis, Autoimmune, Experimental - prevention & control Female Inflammation - drug therapy Inflammation - immunology Inflammation - metabolism Mice Mice, Inbred C57BL Myelin-Oligodendrocyte Glycoprotein - immunology NAD - immunology NAD - metabolism Neurons - drug effects Neurons - immunology Neurons - metabolism Neuroprotective Agents - pharmacology Sirtuin 1 - biosynthesis Sirtuin 1 - immunology Spinal Cord - drug effects Spinal Cord - immunology Spinal Cord - metabolism Stilbenes - pharmacology
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Summary:	Treatment of experimental autoimmune encephalomyelitis (EAE) with resveratrol, an activator of sirtuin 1 (SIRT1), reduces disease severity. This suggested that activators of SIRT1, a highly conserved NAD-dependent protein deacetylase, might have immune-modulating or neuroprotective therapeutic effects in EAE. Previously, we showed that SIRT1 expression increases in EAE, suggesting that it is an adaptive response. In this study, we investigated the potential function of SIRT1 in regulating EAE using SIRT1-overexpressing mice. The current studies examine potential neuroprotective and immunomodulatory effects of SIRT1 overexpression in chronic EAE induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein peptide 35-55. SIRT1 suppressed EAE clinical symptoms compared with wild-type EAE mice and prevented or altered the phenotype of inflammation in spinal cords; as a result, demyelination and axonal injury were reduced. Significant neuroprotective effects were observed, with fewer apoptotic cells found in the spinal cords of SIRT1-overexpressing EAE mice associated with increased brain-derived neurotrophic factor and NAD levels. Earlier, we showed that brain-derived neurotrophic factor and NAD play crucial neuroprotective roles in EAE. These results suggest that SIRT1 reduces neuronal loss in this chronic demyelinating disease model and that this is associated with a reduction in inflammation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-1767 1550-6606
DOI:	10.4049/jimmunol.1202584