Overexpression of SIRT1 Protein in Neurons Protects against Experimental Autoimmune Encephalomyelitis through Activation of Multiple SIRT1 Targets

Abstract

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 nicotinamide adenine dinucleotide (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 (MOG35-55). 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 (BDNF) and NAD levels. Earlier, we showed that BDNF 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.

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

“…Indeed, potent therapeutic effects of resveratrol administration were reported in animal models of Alzheimer's disease and accelerated ageing [10,26,46], multiple sclerosis [47,48], Huntington's disease [9,49], Parkinson's disease [22,50], and even reducing peripheral axonal degeneration [51] or promoting functional recovery after traumatic spinal cord injury [23]. In this sense, resveratrol has been also reported to exert neuroprotection on in vitro models of ALS.…”

SIRT1 in Neurodevelopment and Brain Senescence

“…This protective phenotype was associated with increased brain-derived neurotrophic factor and NAD levels (Nimmagadda et al, 2013). Other studies examining the effect of SIRT1 in adult neuronal precursor pools (NPCs) have not shown as clear a picture regarding the effect of SIRT1 on EAE.…”

“…In adult neuronal precursor cells (NPCs), SIRT1 binds Hes1 under oxidative conditions, inhibiting Mash1 transcription and driving NPCs toward astroglial differentiation (Prozorovski et al, 2008) and increasing the oligodendrocyte population may help remyelinate lesions, reduce axonal damage or decrease astrogliosis. An alternate approach has identified increased BDNF and NAMPT as possible targets to explain neuroprotection due to SIRT1 overexpression in EAE (Nimmagadda et al, 2013). …”

Sirtuin functions in the brain: From physiological to pathological aspects

“…However, Sirt2 overexpression abrogates microtubule hyperacetylation and counteracts resistance to axonal degeneration in cultured cerebellar granule cells from Wld s mice [126] . In EAE, a model for multiple sclerosis (MS), overexpression of Sirt1 improves clinical symptoms with less axonal injury [127] . Sirt1 may also protect against neurodegeneration in both nematode and in vitro models of prion toxicity [128][129][130] .…”