Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease

Microglia are the principal immune cells of the brain. In Alzheimer disease, these brain mononuclear phagocytes are recruited from the blood and accumulate in senile plaques. However, the role of microglia in Alzheimer disease has not been resolved. Microglia may be neuroprotective by phagocytosing amyloid-beta (Abeta), but their activation and the secretion of neurotoxins may also cause neurodegeneration. Ccr2 is a chemokine receptor expressed on microglia, which mediates the accumulation of mononuclear phagocytes at sites of inflammation. Here we show that Ccr2 deficiency accelerates early disease progression and markedly impairs microglial accumulation in a transgenic mouse model of Alzheimer disease (Tg2576). Alzheimer disease mice deficient in Ccr2 accumulated Abeta earlier and died prematurely, in a manner that correlated with Ccr2 gene dosage, indicating that absence of early microglial accumulation leads to decreased Abeta clearance and increased mortality. Thus, Ccr2-dependent microglial accumulation plays a protective role in the early stages of Alzheimer disease by promoting Abeta clearance.     

SIRT1/PGC-1: a neuroprotective axis?

Neurodegenerative diseases are more and more prevalent in our aging societies. A rapid overview of the etiology of many neurodegenerative diseases like Alzheimer, Parkinson, Huntington disease and amyotrophic lateral sclerosis suggests a tight link with mitochondrial dysfunction. Since it has been recently demonstrated that activation of the SIRT1/PGC-1 pathway, in a metabolic context promotes mitochondrial function, we performed a detailed literature review on the implication of this pathway in neurodegeneration. Interestingly, transgenic mice with impaired PGC-1 expression have neurodegenerative lesions and show behavioural abnormalities. As evidenced from independent investigations, enhanced SIRT1 activity has been demonstrated to protect against axonal degeneration and to decrease the accumulation of amyloid beta peptides, the hallmark of Alzheimer disease, in cultured murine embryonic neurons. In addition, several studies suggest that resveratrol, a specific activator of SIRT1, could have protective effects in animal models of neurodegenerative diseases. Taken together, these results strongly suggest that the modulation of the SIRT1/PGC-1 pathway, which has not been well documented in the central nervous system, could become the cornerstone for new therapeutical approaches to combat neurodegeneration.     

beta-Amyloid-induced dynamin 1 degradation is mediated by N-methyl-D-aspartate receptors in hippocampal neurons

Alzheimer disease (AD) is a progressive, neurodegenerative disorder that leads to debilitating cognitive deficits. Although little is known about the early functional or ultrastructural changes associated with AD, it has been proposed that a stage of synaptic dysfunction might precede neurodegeneration in the development of this disease. Unfortunately, the molecular mechanisms that underlie such synaptic dysfunction remain largely unknown. Recently we have shown that beta-amyloid (Abeta), the main component of senile plaques, induced a significant decrease in dynamin 1, a protein that plays a critical role in synaptic vesicle recycling, and hence, in the signaling properties of the synapse. We report here that this dynamin 1 degradation was the result of calpain activation induced by the sustained calcium influx mediated by N-methyl-D-aspartate receptors in hippocampal neurons. In addition, our results showed that soluble oligomeric Abeta, and not fibrillar Abeta, was responsible for this sustained calcium influx, calpain activation, and dynamin 1 degradation. Considering the importance of dynamin 1 to synaptic function, these data suggest that Abeta soluble oligomers might catalyze a stage of synaptic dysfunction that precedes synapse loss and neurodegeneration. These data also highlight the calpain system as a novel therapeutic target for early stage AD intervention.     

SIRT1 Regulates Dendritic Development in Hippocampal Neurons

Dendritic arborization is required for proper neuronal connectivity. SIRT1, a NAD+ dependent histone deacetylase, has been associated to ageing and longevity, which in neurons is linked to neuronal differentiation and neuroprotection. In the present study, the role of SIRT1 in dendritic development was evaluated in cultured hippocampal neurons which were transfected at 3 days in vitro with a construct coding for SIRT1 or for the dominant negative SIRT1H363Y, which lacks the catalytic activity. Neurons overexpressing SIRT1 showed an increased dendritic arborization, while neurons overexpressing SIRT1H363Y showed a reduction in dendritic arbor complexity. The effect of SIRT1 was mimicked by treatment with resveratrol, a well known activator of SIRT1, which has no effect in neurons overexpressing SIRT1H363Y indicating that the effect of resveratrol was specifically mediated by SIRT1. Moreover, hippocampal neurons overexpressing SIRT1 were resistant to dendritic dystrophy induced by Aβ aggregates, an effect that was dependent on the deacetylase activity of SIRT1. Our findings indicate that SIRT1 plays a role in the development and maintenance of dendritic branching in hippocampal neurons, and suggest that these effects are mediated by the ROCK signaling pathway.     

Neuroprotective effect of TNFalpha against the beta-amyloid neurotoxicity mediated by CDK5 kinase

The tumor necrosis factor alpha (TNFalpha) plays a dual role in producing either neurodegeneration or neuroprotection in the central nervous system. Despite that TNFalpha was initially described as a cell death inductor, neuroprotective effects against cell death induced by several neurotoxic insults have been reported. Tau hyperphosphorylation and neuronal death found in Alzheimer disease is mediated by deregulation of the cdk5/p35 complex induced by Abeta treatments. Since TNFalpha affects cdk5 activity, we investigated its possible protective role against the Abeta-induced neurodegeneration, as mediated by cdk5. TNFalpha pretreatments significantly reduced the hippocampal neuronal cell death induced by the effects of Abeta(42) peptide. In addition, this pretreatment reduced the increase in the activity of cdk5 induced by Abeta(42) in primary neurons. Next, we investigated the Alzheimer type phosphorylation of tau protein induced by Abeta(42). We observed that the pretreatment of neurons with TNFalpha reduces tau hyperphosphorylation. Taken together, these results define a novel neuroprotective effect of TNFalpha in preventing neuronal cell death and cdk5-dependent tau hyperphosphorylation. This phenomenon, taken together with other previous findings, suggests that the inflammatory response due to Abeta peptide plays a key role in the development of Alzheimer etiopathogenesis.     

Resveratrol protects cardiomyocytes from oxidative stress through SIRT1 and mitochondrial biogenesis signaling pathways

Reactive oxygen species (ROS) is generated by oxidative stress and plays an important role in various cardiac pathologies. The SIRT1 signaling pathway and mitochondrial biogenesis play essential roles in mediating the production of ROS. SIRT1 activated by resveratrol protects cardiomyocytes from oxidative stress, but the exact mechanisms by which SIRT1 prevents oxidative stress, and its relationship with mitochondrial biogenesis, remain unclear. In this study, it was observed that after stimulation with 50 μM H₂O₂ for 6 h, H9C2 cells produced excessive ROS and downregulated SIRT1. The mitochondrial protein NDUFA13 was also downregulated by ROS mediated by SIRT1. Resveratrol induced the expression of SIRT1 and mitochondrial genes NDUFA1, NDUFA2, NDUFA13 and Mn-SOD. However, the production of these genes was reversed by SIRT1 inhibitor nicotinamide. These results suggest that resveratrol inhibits ROS generation in cardiomyocytes via SIRT1 and mitochondrial biogenesis signaling pathways.     

Amyloid-beta peptides induce cell proliferation and macrophage colony-stimulating factor expression via the PI3-kinase/Akt pathway in cultured Ra2 microglial cells

Alzheimer's disease is characterized by numerous amyloid-beta peptide (Abeta) plaques surrounded by microglia. Here we report that Abeta induces the proliferation of the mouse microglial cell line Ra2 by increasing the expression of macrophage colony-stimulating factor (M-CSF). We examined signal cascades for Abeta-induced M-CSF mRNA expression. The induction of M-CSF was blocked by a phosphatidylinositol 3 kinase (PI3-kinase) inhibitor (LY294002), a Src family tyrosine kinase inhibitor (PP1) and an Akt inhibitor. Electrophoretic mobility shift assays showed that Abeta enhanced NF-kappaB binding activity to the NF-kappaB site of the mouse M-CSF promoter, which was blocked by LY294002. These results indicate that Abeta induces M-CSF mRNA expression via the PI3-kinase/Akt/NF-kappaB pathway.     

Amyloid beta protein activates PKC-delta and induces translocation of myristoylated alanine-rich C kinase substrate (MARCKS) in microglia

The increased accumulation of activated microglia containing amyloid beta protein (Abeta) around senile plaques is a common pathological feature in subjects with Alzheimer's disease (AD). Much less is known, however, of intracellular signal transduction pathways for microglial activation in response to Abeta. We investigated intracellular signaling in response to Abeta stimulation in primary cultured rat microglia. We found that the kinase activity of PKC-delta but not that of PKC-alpha or -epsilon is increased by stimulation of microglia with Abeta, with a striking tyrosine phosphorylation of PKC-delta. In microglia stimulated with Abeta, tyrosine phosphorylation of PKC-delta was evident at the membrane fraction without an overt translocation of PKC-delta. PKC-delta co-immunoprecipitated with MARCKS from microglia stimulated with Abeta. Abeta induced translocation of MARCKS from the membrane fraction to the cytosolic fraction. Immunocytochemical analysis revealed that phosphorylated MARCKS accumulated in the cytoplasm, particularly at the perinuclear region in microglia treated with Abeta. Taken together with our previous observations that Abeta-induced phosphorylation of MARCKS and chemotaxis of microglia are inhibited by either tyrosine kinase or PKC inhibitors, our results provide evidence that Abeta induces phosphorylation and translocation of MARCKS through the tyrosine kinase-PKC-delta signaling pathway in microglia.     

Resveratrol ameliorates sevoflurane-induced cognitive impairment by activating the SIRT1/NF-κB pathway in neonatal mice

Sevoflurane, the most commonly used inhaled anesthetic in pediatric anesthesia, has been reported to induce cognitive impairment in developing brain in preclinical and clinical settings. However, the mechanism and therapeutic measures of this developmental neurotoxicity need to be further investigated. Resveratrol, a natural polyphenolic agent, has been reported to improve cognitive function in neurological disorders and aging models through anti-inflammatory activity. However, its effect on sevoflurane-induced cognitive impairment in developing mice remains unknown. The present study was designed to investigate the therapeutic potential of resveratrol on sevoflurane-induced cognitive impairment. Six-day-old mice received anesthesia with 3% sevoflurane 2 h daily on postnatal days (P) 6, P7 and P8. About 100 mg/kg resveratrol were intraperitoneally administered for 6 consecutive days to neonatal mice before anesthesia. Sevoflurane exposure significantly suppressed the expression of Sirtuin 1 (SIRT1) and activated microglia in hippocampi. Furthermore, the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were markedly increased after sevoflurane exposure. Strikingly, resveratrol pretreatment ameliorated sevoflurane-induced SIRT1 inhibition and microglial activation. Of note, resveratrol reversed sevoflurane-induced imbalance of M1/M2 microglia ratio revealed by increasing mRNA level of clusters of differentiation 206 (CD206) and decreasing mRNA levels of clusters of differentiation 86 (CD86) and suppressor of cytokine signaling 3 (SOCS3). Consequently, sevoflurane-induced cognitive impairment in developing mice was ameliorated by resveratrol pretreatment. Taken together, repeated sevoflurane exposure to the developing brain resulted in SIRT1 inhibition, NF-κB acetylation, and microglial activation. Resveratrol pretreatment ameliorated cognitive impairment in developing mice received sevoflurane exposure by modulating SIRT1-NF-κB pathway in microglia. In this regard, our findings open novel directions to explore promising therapeutic targets for preventing the developmental neurotoxicity of sevoflurane.     

Melatonin reduces interleukin secretion in amyloid-beta stressed mouse brain slices

Neurodegeneration in Alzheimer's disease (AD) is associated with many features of the immune system. For example, cytokines such as IL-6, synthesized by microglia and astrocytes, are associated with senile plaques. To further study the role of cytokines in early stage AD neurodegeneration, an organotypic mouse brain slice culture system with microglia and astrocytes was developed. Amyloid-beta(Abeta1-40) induced the secretion of both IL-1beta and IL-6. Melatonin, an antioxidant and pineal hormone, reduced interleukin secretion in a concentration dependent manner. We also observed that melatonin, alone, had no effect on IL-1beta secretion but at a concentration of 500 microM induced the secretion of IL-6. This organotypic slice system can be used to study the early role of immune system molecules on neurodegeneration.     

Specific inhibition of MyD88-independent signaling pathways of TLR3 and TLR4 by resveratrol: molecular targets are TBK1 and RIP1 in TRIF complex

TLRs can activate two distinct branches of downstream signaling pathways. MyD88 and Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF) pathways lead to the expression of proinflammatory cytokines and type I IFN genes, respectively. Numerous reports have demonstrated that resveratrol, a phytoalexin with anti-inflammatory effects, inhibits NF-kappaB activation and other downstream signaling pathways leading to the suppression of target gene expression. However, the direct targets of resveratrol have not been identified. In this study, we attempted to identify the molecular target for resveratrol in TLR-mediated signaling pathways. Resveratrol suppressed NF-kappaB activation and cyclooxygenase-2 expression in RAW264.7 cells following TLR3 and TLR4 stimulation, but not TLR2 or TLR9. Further, resveratrol inhibited NF-kappaB activation induced by TRIF, but not by MyD88. The activation of IFN regulatory factor 3 and the expression of IFN-beta induced by LPS, poly(I:C), or TRIF were also suppressed by resveratrol. The suppressive effect of resveratrol on LPS-induced NF-kappaB activation was abolished in TRIF-deficient mouse embryonic fibroblasts, whereas LPS-induced degradation of IkappaBalpha and expression of cyclooxygenase-2 and inducible NO synthase were still inhibited in MyD88-deficient macrophages. Furthermore, resveratrol inhibited the kinase activity of TANK-binding kinase 1 and the NF-kappaB activation induced by RIP1 in RAW264.7 cells. Together, these results demonstrate that resveratrol specifically inhibits TRIF signaling in the TLR3 and TLR4 pathway by targeting TANK-binding kinase 1 and RIP1 in TRIF complex. The results raise the possibility that certain dietary phytochemicals can modulate TLR-derived signaling and inflammatory target gene expression and can alter susceptibility to microbial infection and chronic inflammatory diseases.     

Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer's disease

Microglial activation is an important pathological component in brains of patients with Alzheimer's disease (AD), and fibrillar amyloid-beta (Abeta) peptides play an important role in microglial activation in AD. However, mechanisms by which Abeta peptides induce the activation of microglia are poorly understood. The present study underlines the importance of TLR2 in mediating Abeta peptide-induced activation of microglia. Fibrillar Abeta1-42 peptides induced the expression of inducible NO synthase, proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6), and integrin markers (CD11b, CD11c, and CD68) in mouse primary microglia and BV-2 microglial cells. However, either antisense knockdown of TLR2 or functional blocking Abs against TLR2 suppressed Abeta1-42-induced expression of proinflammatory molecules and integrin markers in microglia. Abeta1-42 peptides were also unable to induce the expression of proinflammatory molecules and increase the expression of CD11b in microglia isolated from TLR2(-/-) mice. Finally, the inability of Abeta1-42 peptides to induce the expression of inducible NO synthase and to stimulate the expression of CD11b in vivo in the cortex of TLR2(-/-) mice highlights the importance of TLR2 in Abeta-induced microglial activation. In addition, ligation of TLR2 alone was also sufficient to induce microglial activation. Consistent to the importance of MyD88 in mediating the function of various TLRs, antisense knockdown of MyD88 also inhibited Abeta1-42 peptide-induced expression of proinflammatory molecules. Taken together, these studies delineate a novel role of TLR2 signaling pathway in mediating fibrillar Abeta peptide-induced activation of microglia.     

The GSK3 beta signaling cascade and neurodegenerative disease

Biochemical signaling pathways are known to have a critical role in neuronal development and function. A growing body of evidence is accumulating to suggest that signaling pathways also underlie neurodegeneration and neurodegenerative disease. One pathway with a prominent role in neurodegenerative disease is the signaling pathway in which the enzyme glycogen synthase kinase 3 (GSK3) is a key component. In vitro and in vivo evidence point to a key role for GSK3 in promoting neurodegeneration and in Alzheimer's disease plaque and neurofibrillary tangle formation. How GSK3 acts in this regard is still open to debate, but it may involve both extracellular and nuclear apoptotic activities.     

SIRT1 Negatively Regulates the Mammalian Target of Rapamycin

The IGF/mTOR pathway, which is modulated by nutrients, growth factors, energy status and cellular stress regulates aging in various organisms. SIRT1 is a NAD+ dependent deacetylase that is known to regulate caloric restriction mediated longevity in model organisms, and has also been linked to the insulin/IGF signaling pathway. Here we investigated the potential regulation of mTOR signaling by SIRT1 in response to nutrients and cellular stress. We demonstrate that SIRT1 deficiency results in elevated mTOR signaling, which is not abolished by stress conditions. The SIRT1 activator resveratrol reduces, whereas SIRT1 inhibitor nicotinamide enhances mTOR activity in a SIRT1 dependent manner. Furthermore, we demonstrate that SIRT1 interacts with TSC2, a component of the mTOR inhibitory-complex upstream to mTORC1, and regulates mTOR signaling in a TSC2 dependent manner. These results demonstrate that SIRT1 negatively regulates mTOR signaling potentially through the TSC1/2 complex.     

Dynamic mobilization of PGC-1α mediates mitochondrial biogenesis for the protection of RGC-5 cells by resveratrol during serum deprivation

Mitochondrial dysfunction contributing to the pathogenesis of glaucomatous neurodegeneration has stimulated considerable interest recently. In this study, we explored the role of peroxisome proliferator activated receptor-γ co-activator 1α (PGC-1α) in resveratrol-triggered mitochondrial biogenesis for preventing apoptosis in a retinal ganglion cell line RGC-5. Our results showed that serum deprivation induced cell apoptosis in a time-dependent manner. Applying resveratrol maintained the normal mitochondrial membrane potential, decreased the levels of both total and cleaved caspase-3, and inhibited the release of cytochrome c, which subsequently enhanced cell survival. Moreover, resveratrol stimulated mitochondrial biogenesis by increasing the absolute quantity of mitochondria as well as their DNA copies. Treatment with resveratrol promoted the protein expression of SIRT1, but not PGC-1α; instead, resveratrol facilitated PGC-1α translocation from the cytoplasm to the nucleus and up-regulated NRF1 and TFAM, which were blocked by nicotinamide. Collectively, we demonstrate that the SIRT1-dependent PGC-1α subcellular translocation following resveratrol application potentially attenuates serum deprivation-elicited RGC-5 cell death, thereby raising the possibility of mitigating glaucomatous retinopathy by enhancement of mitochondrial biogenesis.     

Resveratrol‐enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice

Autophagic dysfunction is observed in diabetes mellitus. Resveratrol has a beneficial effect on diabetic cardiomyopathy. Whether the resveratrol‐induced improvement in cardiac function in diabetes is via regulating autophagy remains unclear. We investigated the mechanisms underlying resveratrol‐mediated protection against heart failure in diabetic mice, with a focus on the role of sirtuin 1 (SIRT1) in regulating autophagic flux. Diabetic cardiomyopathy in mice was induced by streptozotocin (STZ). Long‐term resveratrol treatment improved cardiac function, ameliorated oxidative injury and reduced apoptosis in the diabetic mouse heart. Western blot analysis revealed that resveratrol decreased p62 protein expression and promoted SIRT1 activity and Rab7 expression. Inhibiting autophagic flux with bafilomycin A1 increased diabetic mouse mortality and attenuated resveratrol‐induced down‐regulation of p62, but not SIRT1 activity or Rab7 expression in diabetic mouse hearts. In cultured H9C2 cells, redundant or overactive H₂O₂ increased p62 and cleaved caspase 3 expression as well as acetylated forkhead box protein O1 (FOXO1) and inhibited SIRT1 expression. Sirtinol, SIRT1 and Rab7 siRNA impaired the resveratrol amelioration of dysfunctional autophagic flux and reduced apoptosis under oxidative conditions. Furthermore, resveratrol enhanced FOXO1 DNA binding at the Rab7 promoter region through a SIRT1‐dependent pathway. These results highlight the role of the SIRT1/FOXO1/Rab7 axis in the effect of resveratrol on autophagic flux in vivo and in vitro, which suggests a therapeutic strategy for diabetic cardiomyopathy.     

High beta-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-beta levels: implications for the treatment of Alzheimer disease

Amyloid-beta peptides (Abeta) are widely presumed to play a causal role in Alzheimer disease. Release of Abeta from the amyloid precursor protein (APP) requires proteolysis by the beta-site APP-cleaving enzyme (BACE1). Although increased BACE1 activity in Alzheimer disease brains and human (h) BACE1 transgenic (tg) mice results in altered APP cleavage, the contribution of these molecular alterations to neurodegeneration is unclear. We therefore used the murine Thy1 promoter to express high levels of hBACE1, with or without hAPP, in neurons of tg mice. Compared with hAPP mice, hBACE1/hAPP doubly tg mice had increased levels of APP C-terminal fragments (C89, C83) and decreased levels of full-length APP and Abeta. In contrast to non-tg controls and hAPP mice, hBACE1 mice and hBACE1/hAPP mice showed degeneration of neurons in the neocortex and hippocampus and degradation of myelin. Neurological deficits were also more severe in hBACE1 and hBACE1/hAPP mice than in hAPP mice. These results demonstrate that high levels of BACE1 activity are sufficient to elicit neurodegeneration and neurological decline in vivo. This pathogenic pathway involves the accumulation of APP C-terminal fragments but does not depend on increased production of human Abeta. Thus, inhibiting BACE1 may block not only Abeta-dependent but also Abeta-independent pathogenic mechanisms.     

SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis

A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.     

Microglia-mediated nitric oxide cytotoxicity of T cells following amyloid beta-peptide presentation to Th1 cells

Alzheimer's disease is marked by progressive accumulation of amyloid beta-peptide (Abeta) which appears to trigger neurotoxic and inflammatory cascades. Substantial activation of microglia as part of a local innate immune response is prominent at sites of Abeta plaques in the CNS. However, the role of activated microglia as Abeta APCs and the induction of adaptive immune responses has not been investigated. We have used primary microglial cultures to characterize Abeta-Ag presentation and interaction with Abeta-specific T cells. We found that IFN-gamma-treated microglia serve as efficient Abeta APCs of both Abeta1-40 and Abeta1-42, mediating CD86-dependent proliferation of Abeta-reactive T cells. When cultured with Th1 and Th2 subsets of Abeta-reactive T cells, Th1, but not Th2, cells, underwent apoptosis after stimulation, which was accompanied by increased levels of IFN-gamma, NO, and caspase-3. T cell apoptosis was prevented in the presence of an inducible NO synthase type 2 inhibitor. Microglia-mediated proliferation of Abeta-reactive Th2 cells was associated with expression of the Th2 cytokines IL-4 and IL-10, which counterbalanced the toxic levels of NO induced by Abeta. Our results demonstrate NO-dependent apoptosis of T cells by Abeta-stimulated microglia which may enhance CNS innate immune responses and neurotoxicity in Alzheimer's disease. Secretion of NO by stimulated microglia may underlie a more general pathway of T cell death in the CNS seen in neurodegenerative diseases. Furthermore, Th2 type T cell responses may have a beneficial effect on this process by down-regulation of NO and the proinflammatory environment.     

The controversial links among calorie restriction, SIRT1, and resveratrol

It has been widely known that slow metabolism induced by calorie restriction (CR) can extend the life span of model organisms though the underlying mechanism remains poorly understood. Accumulated evidence suggests that SIRT1 may be actively involved in CR-induced signaling pathways. As a putative activator of SIRT1, resveratrol, known for the French paradox, can partially mimic the physiological effects of CR. While the deacetylase activity of SIRT1 is important for the beneficial effects of resveratrol, resveratrol-induced SIRT1 activation has recently been challenged by the observations that resveratrol could not induce SIRT1-mediated deacetylation of native substrates in vitro. To resolve the discrepancy of resveratrol-induced activation of SIRT1 deacetylase activity between the in vitro and in vivo assays, a model of indirect SIRT1 activation by resveratrol is proposed. In this review, we will discuss the emerging roles of SIRT1 and resveratrol in CR and focus on debate over the links between SIRT1 and resveratrol.