Jing Yan
Xiaole Tang2
Zhi-qiang Zhou
Jie Zhang
Yilin Zhao
Shiyong Li
Ailin Luo- 1Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- 2Department of Anesthesiology, Sun Yat-sen University Cancer Center, Guangzhou, China
The sirtuins (SIRTs), a class of NAD+ -dependent deacylases, contain seven SIRT family members in mammals, from SIRT1 to SIRT7. Extensive studies have revealed that SIRT proteins regulate virous cell functions. Central nervous system (CNS) decline resulted in progressive cognitive impairment, social and physical abilities dysfunction. Therefore, it is of vital importance to have a better understanding of potential target to promote homeostasis of CNS. SIRTs have merged as the underlying regulating factors of the process of neurological disorders. In this review, we profile multiple functions of SIRT proteins in different cells during brain function and under CNS injury.
Introduction
SIRTs in mammals are a class of proteins that possess NAD + dependent deacetylase activity or ADP-ribosyltransferase activity varies from SIRT1 to SIRT7. These SIRTs are present in different tissue and subcellular localization: SIRT1 and SIRT2 are expressed in the nucleus and cytoplasm, whereas SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 localized only in the nucleus (Cai et al., 2016). The initial studies found Sir2 protein contributes to lifespan extension in yeasts, worms and flies in which Sir2 and its orthologs mediated caloric restriction-induced extension of lifespan in certain genetic backgrounds (Li et al., 2007). However, mice overexpressing SIRT1 did not show lifespan extension. Striking, whole-body SIRT6 transgenic mice showed lifespan extension in males (Zorrilla-Zubilete et al., 2018). Later studies indicated SIRTs’ protect brain function in virous mammalian models. Recent evidence showed that SIRTs exert anti-aging and neuroprotective effect through regulating diverse cell functions and responses to stressors (Herskovits and Guarente, 2014). Herein we review multiple functions of SIRT proteins during maintaining normal cellular function in central nervous system.
SIRT1 in neurons in central nervous system
Sirtuin 1 (SIRT1) is a member of the nicotinamide adenine dinucleotide (NAD)+-dependent class III histone deacetylases, which is the studied one among the SIRT family (Gomes et al., 2018). Mounting Data suggest SIRT1 to be an important factor involved in a vast physiological and pathological role in brain through modulating variety of molecular signaling pathways essential for central nerves system homeostasis and normal brain function. In mammalian cells, SIRT1 located in nucleus and cytoplasm. Within the nucleus, SIRT1 regulates transcription process through promoting histone deacetylation and modulating DNA methylation. Within the cytoplasm, SIRT1 participates in regulating various cellular processes, such as cell apoptosis, oxidative stress, autophagy, endoplasmic reticulum stress and mitophagy.
Some studies suggest that cytoplasm-localized SIRT1 promotes apoptosis, while the anti-apoptotic effect attributes to the nuclear-localized SIRT1. Research indicated that SIRT1 plays a pivotal role in alleviating apoptosis. Upregulated SIRT1 alleviated manganese-induced neuronal apoptosis through activation of FOXO3a, and activated expression of SIRT1 also alleviating the apoptosis of mouse hippocampal neurons (HT22) cells through facilitating the deacetylation and phosphorylation of FOXO3a (Zhao et al., 2021a). Mostly, SIRT1 exerts neuroprotective effect through reducing apoptosis. However, nicotinamide, a pharmacological inhibitor of SIRT1, enhances neuronal survival and reduces apoptosis during acute anoxic injury, implying the benefit of SIRT1 deficiency, seemly indicate that SIRT1 might play a detrimental role (Chong and Maiese, 2008). Pharmacological or genetically downregulated SIRT1 significantly reduced ERK1/2 activation and promoted apoptotic neuron death both in vitro and in vivo of traumatic brain injury models (Zhao et al., 2012). SIRT1 deficiency in neuron leads to the acetylation of p53, a critical transcriptional factor that controls apoptotic programs and also the first nonhistone deacetylation target for SIRT1, thereby instigating neuronal death in cerebral ischemic stroke mice (Chen et al., 2014).
SIRT 1 has a vital role in autophagy stimulation through deacetylating autophagy-related proteins including FoxO, Atg5, Atg7, and Atg8 (Hariharan et al., 2010). Also, SIRT1 is a major deacetylase for BECN1 K430 and K437, which form multiple protein complexes participating in autophagy (Xu and Wan, 2022). Oxidative stress could decrease SIRT1 enzymatic activity and protein stability through promoting SIRT1 cysteinyl carbonylation on Cys482, and SIRT1-deficient cells are more sensitive to exogenous H2O2 that could induce autophagy (Zhou et al., 2022a). SIRT1 activation plays a pivotal role protecting against prion-induced neuronal death through regulating autophagy process (Jeong et al., 2013). In a cardiac arrest-related brain injury, researchers used a SIRT1 loss of function approach and found that suppression of SIRT1 compromised the neuroprotection by mild hypothermia treatment both in vivo and in vitro through mediating autophagic flux, they came up with the idea that FOXO1, a transcription factor binds to several consensus sites on the SIRT1 promoter and enables its transcription, might be the upstream of SIRT1 in this model, and further investigation is warranted (Wei et al., 2019).
Accumulating evidence has indicated that SIRT1 function is tightly related to axon genesis and neurite outgrowth. SIRT1 deficiency could cause synaptic plasticity impairment and cognitive dysfunction (Cai et al., 2016). SIRT1 regulates transcription factors, including nuclear factor-E2-related factor 2 (Nrf2), a major regulator in antioxidant defenses, to exert a neuroprotective effect by inducing neurite outgrowth in Neuro-2a cells (Duangjan et al., 2021), peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), a fasting-induced transcriptional coactivator recruited during PPAR stimulation, to restore neuronal network disconnection through reversing synaptic failure in hippocampal neuron in vitro (Panes et al., 2020). In neonatal propofol exposure experiment, SIRT1 was tightly related to synaptic plasticity and neuronal excitability in the hippocampal CA1 region (Ma et al., 2022).
SIRT1 also take parts in physiological and pathological process correlated to neuronal cell damage such as oxidative stress, metabolic disorders and calcium homeostasis. It has been reported that SIRT1 counteracts the activation of acetyl-STAT3 (Lys685) and increase neural senescence and affects locomotor behavior (Liu et al., 2021a). SIRT1/PGC-1α pathway relieving neuronal oxidative stress through activating mitochondrial biogenesis against Aβ1-42 oligomer-induced oxidative stress (Yin et al., 2021a). As SIRT1 mediated caloric restriction, study on unhealthy-diet-induced learning and memory loss found that biogenesis related genes SIRT1 and PGC1α upregulated along with reversed high-glucose-induced oxidized cellular status, mitochondrial membrane impairment, insulin signaling inhibition and neuron damage in high-fat and high-fructose feed mice (Liu et al., 2017). Compelling investment revealed that SIRT1 provides neuroprotection by promoting calcium regulation in neurons (Stoyas et al., 2020). In a PD mice model, SIRT1 was found downregulated in neuron, which leading to FOXO1 acetylation upregulation, and subsequently increased the transcription level of type A monoamine oxidase (MAO-A), an enzyme primarily engaged in catalyzing the oxidative deamination of NA and 5-HT and leading to inactivation and degradation of both monoamines. Activation SIRT1 by resveratrol restored brain NA and 5-HT levels and attenuates the depressive-like behavior (Li et al., 2020a). The effect of SIRT1 changing the acetylation status of BMAL1 and PER2 and further affecting their activity and stability respectively, is involved in the metabolism mechanism of circadian machinery (Asher et al., 2008). Later, Aras et al. provide in vivo evidence that SIRT1 deficiency in neurons within the hypothalamic ventromedial nucleus are more prone to develop metabolic imbalance (Ramadori et al., 2011). What’s more, they also found that SIRT1 in neurons within the hypothalamic ventromedial nucleus convey photic inputs to entrain the biochemical and metabolic action of insulin in skeletal muscle in mice (Aras et al., 2019).
In hypoxia-ischemia rat, SIRT1 expression significantly reduced in neuron, and was related to the increased ER stress and neurotoxicity due to its action in the modulation of a wide variety of signaling pathways involved in neuroprotection (Carloni et al., 2014). In our previous studies, SIRT1 overexpression could reduce tau acetylation and thus preserve cognitive function in mice following anesthesia and surgery (Yan et al., 2020). Later, our team investigate the role of neuronal SIRT1 in developing mice exposed to volatile anesthetic sevoflurane, we found that SIRT1 epigeneticlly regulated the activity of MeCP2 and CREB, therefor affect the expression of BDNF, which is a vital factor for normal neuronal function (Tang et al., 2020).
SIRT1 in microglia in central nervous system
Microglia are immune cells of the resident macrophages in the brain, which is continually involved in surveillance of the brain parenchyma, and providing as the first line of defense against disease-causing pathogenic stimuli. Mountings of findings indicated that SIRT1 deficiency could injury normal function of microglia (Meng et al., 2020). Mitochondria dysfunction linked neurodegeneration and neuroinflammation via coordinating innate and adaptive immune responses, and initiate and promoted the activation of microglia through increase reactive oxygen species (ROS). It has been reported that SIRT1 regulates PGC-1α by increasing its expression and decreasing its acetylation in microglia at least in part rescued mitochondria injury, decreased ROS production, and reduced neuroinflammatory response which ultimately ameliorated the cognitive dysfunction in chronic cerebral hypoperfusion models in vivo and in vitro (Zhao et al., 2021b). PGC-1α, a major regulator of ROS metabolism and mitochondria biogenesis, has also been proved to be downstream of SIRT1 in post-neonatal hypoxic–ischemic encephalopathy rat (Xie et al., 2021). HMGB1/NF-kB pathway also might be downstream of SIRT1 to inhibit microglia activation and proinflammatory cytokines release in subarachnoid hemorrhage rats and LPS treated BV2 cells (Wang et al., 2019; Zhang et al., 2020a; Li et al., 2020b).
Chronic and persistent activation of microglia has been proved to drive cells in the central nerves system to senescence phenotype through senescence-associated beta-galactosidase (SA β-gal) activity upregulation, growth arrest, and senescence-associated secretory phenotypes (SASPs) which involves uncontrolled secretion of proinflammatory cytokines, which exhibit detrimental effects on cells (Hardeland, 2019). SIRT1 was reduced in aging brain and associated with the impairment of learning and memory (Chaudhuri et al., 2013; Meng et al., 2020). In our previous work, we found that SIRT1 expression significantly decreased in anesthesia and surgery treated aged mice, and upregulated SIRT1 could significantly reduce microglia activation-related neuroinflammation and ameliorated cognitive impairment through regulating the expression of DNMT1 and ac-NF-κB (Yan et al., 2019). Our result is consistent with a previous study that SIRT1 deficiency in microglia contribute to aging and neurodegeneration-related cognition decline, importantly, in this article, they proved that SIRT1 exert neuroprotection through hypomethylating the specific CpG sites on IL-1β proximal promoter which is a classic inflammatory factor (Cho et al., 2015). Later, our team investigated SIRT1/NF-κB signaling in developing mice, as expected, we found that SIRT1 overexpression inhibited microglial activation and improved the long-term cognitive function through decreasing the expression of ac-NF-κB (Tang et al., 2021). In early 2005, Li Gan and his group have indicated that overexpression of SIRT1 deacetylase increased acetylation of RelA/p65 at lysine 310 and regulates the NF-κB pathway in amyloid-β peptides treated primary microglia (Meng et al., 2020). Recent research confirmed that in BV2 cells, reduced SIRT1 expression caused an increased inflammatory response in microglia termed as M1 polarization and promoted microglial migration (Yin et al., 2021b), and suppressed acetylation of NF-κB p65 subunit by SIRT1 in BV-2 microglia decreased the inflammatory factors, including TNF-α and IL-6 (Qin et al., 2020; Zhu et al., 2020). Besides, SIRT1 exerted protection against hypoxic-derived neuronal damage through regulating NF-κB (Merlo et al., 2020). And activated SIRT1/FOXO1 pathway could also reduce microglia activation and inflammatory response (Zhang et al., 2021a). SIRT1 down-regulated the level of Ac-NFκB expression and then suppressed the expression of pro-inflammatory cytokines, accompanied by the decreased activation of microglia, to withhold the cognitive function in mice (Pan et al., 2018). Furthermore, downregulated SIRT1 level prevented M2 microglial polarization and promote motor and nonmotor deficits in Parkinson’s disease (PD) mice (Yang et al., 2021).
The anti-inflammatory effect of SIRT1 has also been explored in several neurodegenerative diseases. In Parkinson’s disease models, SIRT1 signaling pathway is involved in NLRP3 inflammasome activation in microglia (Zheng et al., 2021), that has been proved again in an subarachnoid hemorrhage mice model in which SIRT1 not only involved in microglia activation, but also M2 microglial polarization (Zhang et al., 2021b). In aluminum chloride treated mice, SIRT1 regulated DDX3X-NLRP3 Inflammasome signaling pathway (Hao et al., 2021). Other substrate of SIRT1 such as NF-κB has been found changed and involved in microglial polarization in Parkinson’s disease models (Yang et al., 2021). In Alzheimer’s disease models, SIRT1 directly interacted with and deacetylated TFEB at lysine residue 116 to enhanced lysosomal function and fAβ degradation, thus attenuating amyloid plaque deposition in APP/PS1 transgenic mice (Bao et al., 2016).
SIRT1 has been found neuroprotective in other neurological disorders such as microgliopathic pain, which might be stimulated by activated microglia induced abnormal discharge of neurons, via its anti-inflammatory effect (Wen et al., 2021); and radiation-induced brain injury, in which SIRT1 exert protective effect through reducing oxidative stress damage, inflammation and microglial infiltration (Liu et al., 2021b); and chronic unpredictable mild stress mice model, in which SIRT1 signaling exerted antidepressant effect through modulating NLRP3 inflammasome deactivation (Tong et al., 2020); and brain injury in epilepsy and acute ethanol intoxication, in which SIRT1 prevented astrocytes and microglia activation, as well as inhibition of oxidative stress (Khan et al., 2018; Kong et al., 2020); and LPS treated neonatal mice, in which SIRT1/Nrf2 signaling pathway activation reduced LPS-induced oxidative stress damage, acute neuroinflammation, and apoptotic neurodegeneration (Shah et al., 2017). Researches also demonstrated that SIRT1 deficiency in microglia caused neuroinflammation, subsequently impaired neuronal function through apoptosis, autophagy, et al. (Liu et al., 2019).
SIRT1 in astrocytes in central nervous system
Astrocytes perform various functions in central nerves system including immunity modulation, transmitter uptake and regulation, brain structures support, blood-brain barrier permeability regulation. Downregulation of SIRT1 is reported to be related with astrocytes activation in PD model, AD model and traumatic brain injury model (Scuderi et al., 2014; Abd El-Fatah et al., 2021; Zhang et al., 2021c; Har-Even et al., 2021; Yang et al., 2022). HIV-associated neurocognitive disorders presented in almost 50% of the infected individuals, it was founded downregulated SIRT1 expression in the HIV Tg rats with a concomitant increase in astrocyte marker (Hu et al., 2017). Astrocytic SIRT1 inhibition significantly increased the acetylation of forehead box protein O4, decreased the expression of superoxide dismutase two and catalase, and increased reactive oxygen species production in vitro (Cheng et al., 2014). Confocal imaging showed that SIRT1 upregulated by resveratrol increased the expression of LC3 in astrocytes around the lesion site after injury in traumatic brain injury mice (Zhang et al., 2019a). In brain injury model, elevated SIRT1 levels by resveratrol significantly increases the level of p-ERK but reduces the levels of p-JNK and p-p38 protein, thus attenuated astrocyte activation (Li et al., 2017). Also, SIRT1 upregulation was accompanied with downregulated mRNA expression of pro-inflammatory cytokines, including TNF-α and IL-1β, decreased activation of astrocytes and ameliorated blood-brain barrier disruption in ischemic brain of mice (Li et al., 2020c).
As astrocyte activation precedes extracellular Aβ deposition, an AD research focused on astrocyte function, and they found that SIRT1 could enhance the ability of astrocytes to clear Aβ, and subsequently essentially delay the formation of amyloid deposits via deacetylating several lysosome-related proteins and upregulate lysosome number (Li et al., 2018). In chronic cerebral hypoperfusion rat model, AMPK/SIRT1 signaling was reduced along with increased expression of STAT3/NF-κB pathway (Li et al., 2020d). Other substrate of SIRT1 in astrocytes has been revealed. SIRT1 plays a protective role against astrocyte activation through interaction with Dnajb1 and modulate the deacetylation and ubiquitination of Dnajb1 in vivo and in vitro model of traumatic brain injury (Zhang et al., 2022). In cerebral ischemia/reperfusion injury model, SIRT1 directly mediated the PGC-1α/PPARγ pathway in astrocytes, attenuated oxidative stress injury and therefore reversed the neurological deficit (Zhou et al., 2022b).
SIRT1 in oligodendrocytes in central nervous system
Oligodendrocyte precursors differentiate into mature myelin forming oligodendrocytes to preserve the balance between demyelination and remyelination, which keep the myelin sheath renewal and the axons in a normal status, thus support neuron nutrition in the central nervous system (Prozorovski et al., 2019; Hisahara et al., 2021). As mature and terminally differentiated cells that form myelin sheaths around axons, oligodendrocyte are found predominantly, but not exclusively, in CNS white matter, and could produce myelin sheaths that allow “saltatory” action potential propagation, therefor greatly increases conduction velocity, speeding the efficiency of communication between CNS neurons (Zhou et al., 2021). In an exercise training and dietary fat interplay mice model, SIRT1, PGC-1α and antioxidant enzymes were increased and contribute to mitochondrial activity in oligodendroglia in response to higher levels of reactive oxygen species (Yoon et al., 2016). SIRT1 regulated oligodendrocyte regeneration via deacetylating retinoblastoma in the Rb/E2F1 complex, leading to E2F1 dissociation in neonatal brain injury mice (Jablonska et al., 2016). In a mouse model of multiple sclerosis, increased oligodendrocyte generation and decreased apoptosis were consistent with increased SIRT1 expression (Mojaverrostami et al., 2020). It was observed that SIRT1 co-localizes with surviving oligodendrocytes in multiple sclerosis plaques, then the research group found a significant reduction in phospho-SIRT1 and SIRT1 expression during oligodendrocytes differentiation, associated with decreased expression of H3K9me3 and increased cyclin D1 (Tatomir et al., 2020). Taken together, SIRT1 promoted oligodendrocytes differentiation and regeneration in the CNS.
SIRT2 in central nervous system cells
SIRT2 is predominantly cytosolic and shuttle between the cytoplasm and nucleus. Several studies indicated an important role of SIRT2 in cognitive and brain function. SIRT2 localized to the outer and juxtanodal loops in the myelin sheath and has a counterbalancing role on oligodendroglial differentiation (Li et al., 2007). Fang N found that SIRT2 translocated into the nuclei, epigeneticly downregulated PDGFRα expression and facilitate the differentiation of oligodendroglial cell line (Fang et al., 2019).
ATP homeostasis in axons is highly vulnerable to bioenergetic failure, and is required in neuron function. In vivo research revealed that of SIRT2 transcellular oligodendrocyte-to-axon delivery enhances ATP production by deacetylating mitochondrial proteins and enhanced axonal energy in mice (Chamberlain et al., 2021). SIRT2 is highly expressed in oligodendrocytes and be released within exosomes. Still, there are few researches found SIRT2 expressed in neurons. Genetic or pharmacologic SIRT2 inhibition reduced sterol levels via decreased nuclear SREBP-2 trafficking and showed neuroprotective effect in a striatal neuron model of HD (Luthi-Carter et al., 2010).
On the other hand, SIRT2 inhibition has been proved beneficial in some neurodegenerative mouse model. Pais TF reported, for the first time, that SIRT2 is also expressed in microglia and the absence of SIRT2 enhanced microglia activation associated with a proinflammatory phenotype induced by LPS in BV2 cells (Pais et al., 2013). Compelling evidence indicated that SIRT2 accumulates in several microglia models. SIRT2 increased lipopolysaccharide-induced microglial activation in vivo and in vitro through regulation of MAKP signaling and inflammatory response including a major inflammation transcription regulator, the p65 subunit of NF-kB (Chen et al., 2015a; Jiao et al., 2020),besides, SIRT2 showed potential effect on intracellular ATP levels through poly (ADP-ribose) polymerase (PARP) activation in microglia cell line (Li et al., 2013). Animal study showed that SIRT2 also promote sevoflurane-induced learning and memory deficits in the developing rat brain. SIRT2 inhibitor, AK7, pretreatment protected against sevoflurane-mediated cognitive impairments possibly by enhancing the proportion of M2-phenotype microglia (Wu et al., 2020). However, AK7, the brain-permeable SIRT2 inhibitor, which showed neuroprotective effect in neurodegenerative disease including Parkinson’s disease and Huntington’s disease by protecting dopaminergic neurons against aSyn-induced neurotoxicity in vitro and promotes long-term survival of dopaminergic neurons in vivo, does not show beneficial effects in amyotrophic lateral sclerosis and cerebral ischemia mouse model (Chen et al., 2015b). Furthermore, studies have reported that AK7 is not beneficial under conditions where the control of the microglial response is crucial for neuronal survival, and the anti-inflammatory properties of SIRT2 through post-translational deacetylation of p65 might be a underlying mechanism (Romeo-Guitart et al., 2018). Not only in microglia, in rat primary astrocytes, SIRT2 inhibition partly induced cellular senescence through increase senescence-associated β-galactosidase (SA-β-gal) activity, senescence-associated secretory phenotypes and cell cycle-related proteins (Bang et al., 2019).
SIRT3 in neurons in central nervous system
Sirtuin-3 (SIRT3), localized in the mitochondria, is a NAD+-dependent deacetylase. SIRT3 exerts protection against the progression of cognitive dysfunction through regulates mitochondrial energy metabolism, antioxidant mechanisms, inflammation, autophagy, and cell death processes via targeting of the involved enzymes (Almalki et al., 2021). Mitochondria are small double-membrane organelles which could provide energy for cellular functions. Mitochondrial dysfunction has reported as a significant determinant in brain dysfunction pathophysiological processes (Song et al., 2013). SIRT3 can deacetylate and activate LKB1 (liver kinase B1), and active LKB1 can phosphorylate AMPK to activate AMPK (Liu et al., 2020). In ischemic-injured PC12 cells, promoting SIRT3/AMPK pathway significantly increased cell survival, decreased apoptosis rate and increased the mitochondrial autophagy (Li et al., 2021). It has been reported that increased SIRT3 providing neuroprotective effects via enhancing mitochondrial function, increase neuron survival and decrease the number of apoptotic neurons in cerebral ischemia rat through activation of the SIRT3/AMPK/mTOR pathway (Liu et al., 2020). In addition, SIRT3 alleviated cell death and promoted cell viability of the HT22 cells through preservation of mitochondrial function (Lin et al., 2021). Cerebral ischemia-reperfusion injury caused neuron apoptosis, SIRT3 overexpression attenuated neuron apoptosis possibly through blocking caspase-9-dependent mitochondrial apoptotic signals and suppressed mitochondrial fission via activating the Wnt/β-catenin pathway in vitro and in vivo (Zhao et al., 2018).
SIRT3 played a positive role in promoting autophagy in HT22 cells to resist from the neurotoxicity induced by Aβ1–42 oligomers through increasing Beclin-1 and LC3-II expression, as well as led to the p62 expression (Zhang et al., 2020b). In a subarachnoid hemorrhage mice model, SIRT3 exerted anti-apoptotic effect on neuron through deacetylated SOD to decrease neuron lose (Zhang et al., 2019b). In Aβ42 treated APPTG mice, SIRT3 activity and expression was found to be decreased and be associated with hippocampal neuron cell apoptosis and cognition deficit (Liu et al., 2021c). Besides, SIRT3 has been reported as neuroprotective in ALS models (Harlan et al., 2020). However, the underline mechanism of SIRT3 in these processes still needs further investment. In a high-fat diet mice model, the hippocampus plasticity was reduced and spatial learning function was compromised, SIRT3 upregulation could decrease hippocampal neuron oxidative stress and apoptosis to attenuates high-fat diet-associated cognitive dysfunction through acetylate antioxidative MnSOD (Shi et al., 2018). In an ischemia research, SIRT3 SUMOylation triggered by SENP1 subsequently results in increased levels of COX1, SOD2, and IDH2 protein acetylation, which caused oxidative stress and mitochondrial dysfunction in vitro and in vivo (Cai et al., 2021).
In a study of SIRT3-depleted mice, the behavioral phenotypes have been explored, they found that locomotion, anxiety, and recent memory of the mice remain normal, but the remote memory was impaired, this consist with impaired long-term potentiation in the anterior cingulate cortex which might due to neuronal loss (Kim et al., 2019). It has been reported that SIRT3 reduction caused aggravated GABAergic neuron loss and neuronal network hyperexcitability in Sirt3+/−AppPs1 mice (Cheng et al., 2020). Besides, SIRT3 was found increased in substantia nigra after physical exercise which might be related to an increase in expression of the protective Ang 1-7/Mas axis and inhibition of the Ang II/AT1 axis (Munoz et al., 2018). Although these results suggest that SIRT3 is protective in neuronal function in various manners including neuronal apoptosis, autophagy, mitochondrial function preservation, neuronal network hyperexcitability, future investigations are necessary to confirm the underline signaling pathways.
Research on cardiomyopathy revealed that PGC-1α plays a role in moderating SIRT3, which in turn deacetylates enzymes to control antioxidants and the metabolization of mitochondrial energy (Zhu et al., 2020). Similarly, PGC-1α/SIRT3 pathway have been reported neuroprotective in hippocampus by preventing damage to mitochondria and preventing cell apoptosis and neuron loss (Cheng et al., 2021). As we have discussed in 1.1, SIRT1 has been proved to be downstream of SIRT1, thus SIRT1/PGC-1alpha/SIRT3 pathway might play an essential role in mitochondrial dysfunction, oxidative stress and related neurological deficits. (Cheng et al., 2021).
SIRT3 in microlgia in central nervous system
SIRT3 overexpression in mouse primary microglia prevented the microglia senescence through decreasing the expression of mitochondrial antioxidant enzymes (Thangaraj et al., 2021). In a study of PD cell model, they found that decreased expression of SIRT3 underlines the pathological process of microglia activation resulted oxidative stress injury, membrane potential depolarization and mPTP opening mediated cell apoptosis in dopaminergic neurons (Jiang et al., 2019). In addition, SIRT3 exerted an anti-apoptotic effect in LPS-treated BV2 cells through suppressing the transcription of SRV2 via the Mst1-JNK pathway and thus suppressed mitochondrial fission. (Zhou and Jiang, 2019) Besides, Yun Yuan and his group found that SIRT3 expression could be inhibited by Notch signaling pathway interference in microglia, and that SIRT1 and Notch synergistically regulate microglia activation including TNF-α production (Guo et al., 2021). Several SIRT3 substrates have been reported involved in mitochondrial biogenesis and dynamism pathways dependent pathological mechanisms (Liu et al., 2021d). In mouse primary microglial, overexpression of SIRT3 prevented HIV Trans-activator of transcription mediated imbalance of mitochondrial oxidative stress and induction of senescence phenotype (Thangaraj et al., 2021).
In an ischemia animal model, SIRT3 expression was found to be increased in macrophages, and increased SIRT3 promoted microglial N9 cells migration by upregulating CX3CR1 (Cao et al., 2019). Activated microglia caused uncontrolled production of ROS which forms an important basis for microglia-mediated neurodegeneration and associated cognition deficit. It was reported that microglial SIRT3 upregulation facilitates the increase in Foxo3a expression and its nuclear localization to carry out its antioxidant-mediated attenuation of ROS. The researchers reassured SIRT3 as the upstream regulator of Foxo3a in microglia using Sirt3−/− mouse (Rangarajan et al., 2015). In 2021, Yu-Qing Wu and his group found that SIRT3 suppressed hippocampal neuroinflammation and exert protection in anesthesia/surgery-induced cognitive decline in aged mice through ameliorating the anesthesia/surgery-induced mitochondrial oxidative stress response, microglia activation and neuroinflammation (Liu et al., 2021d). In a study of Alzheimer’s Disease, researchers found that SIRT3 deficiency caused microglia activation following exposure to a combination of high glucose and palmitic acid using SIRT3 shRNA Lentiviral particles in BV2 cells, and enhanced microglial and endothelial interactions which may leading to BBB breakdown, and thus caused cognitive dysfunction, however, the mechanism of SIRT3 deficiency under microglial and endothelial interactions has not been further exacerbated (Tyagi et al., 2021).
SIRT3 in astrocytes and oligodendrocytes in central nervous system
It was reported that SIRT3 mediated the inhibitory effect of adjudin in astrocyte activation and glial scar formation in mouse model of transient middle cerebral artery occlusion and in primary astrocytes (Yang et al., 2017). Knockdown of SIRT3 using specific siRNA (Si-Sirt3) partially reserved the effects of AMPAR antagonist on neuronal injury and BBB function in vitro neurovascular unit (NVU) system including neurons, astrocytes, and brain microvascular endothelial cells (Chen et al., 2021). what’s more, SIRT3 also act as a factor regulating non-cell-autonomous neuronal death through glia. SIRT3 overexpression suppressed oxidative stress-induced neuronal toxicity in SH-SY5Y cells while SIRT3 deficiency promoted rotenone- or H2O2-induced neuronal toxicity in differentiated SH-SY5Y cells (Lee et al., 2021).
Seldom studies focusing on investigating the role of SIRT3 in astrocytes and oligodendrocytes. Further study is required to determine roles of SIRT3 in the two types of glia cells.
SIRT4/5 in central nervous system cells
SIRT4 and SIRT5 both localize in mitochondria. SIRT4 is an ADP-ribosyltransferase whereas SIRT5 is a desuccinylase and demalonylase with weak deacetylase activity (Kida and Goligorsky, 2016). In hepatic encephalopathy, overexpression SIRT4 in astrocyte inhibited GDH2 activity and restored mitochondrial respiration (Drews et al., 2020), which suggests SIRT4 exert a protective effect in astrocyte. In an AD model, the expression of SIRT5 was significantly decreased, along with suppressed autophagy in neuron. Overexpression of SIRT5 in glia cells repressed microglia and astrocyte activation, and restored oxidative stress-induced brain damage (Wu et al., 2021). Currently investigations focused on SIRT4 and SIRT5 in CNS are rare.
SIRT6 in central nervous system cells
SIRT6 is a chromatin-associated protein that stabilizes genomes and prevents cell premature senescence. In mice cortical and hippocampal primary neurons, SIRT6 is closely related with synaptic function, neuronal maturation and neuronal survival (Cardinale et al., 2015). Another study indicated that SIRT6 levels affect synaptic plasticity and neuronal survival via regulating Akt-GSK3β signaling, moreover, upregulated SIRT6 is related to depression-like behavior, which indicated that SIRT6 might exert neurotoxic effect on neuron (Mao et al., 2017) Another study on PD suggest that SIRT6 plays a pathogenic and pro-inflammatory role (Nicholatos et al., 2018). On the other hand, decreased SIRT6 expression has been found in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, enhancing the activity or expression of SIRT6 abrogates its neurotoxicity in cell culture models of ALS (Harlan et al., 2020). In an ischemic stroke model, LPS-stimulated inflammatory response in primary mouse microglia can be inhibited by SIRT6 activation (He et al., 2021). The dual effect of SIRT6 in central nervous system may due to different pathological context. Currently it is not fully elucidated whether SIRT6 is protective in CNS.
SIRT7 in central nervous system cells
SIRT7 is the only SIRT protein localized predominantly in the nucleoli (Wang et al., 2020). In cerebral ischemia/reperfusion injury cell model, overexpression of SIRT7 protect neurons possibly through regulating p53-mediated proapoptotic signaling pathway (Lv et al., 2017). SIRT7 knockdown mice proved slight protective effect through regulating cell differentiation and cytokine production via reducing peripheral IFN-γ production and failed accumulation of regulatory T cells in the CNS. Besides, SIRT7 promoted adult-born neurons survival but had no effect on hippocampal neurons proliferation (Burg et al., 2018). Future investigations are need to clarify the SIRT7 function in CNS.
Discussion
The fact that sirtuins play important roles in maintaining normal cellular function to keep the homeostasis of CNS, makes them an attractive candidate to be fully investigated in central nervous system cells. As described above, the sirtuins are involved in regulating essential cell function including oxidative stress, cell mitigation, apoptosis, mitochondrial function, et al. The majority of the mammalian sirtuins exert neuroprotective effect in the cells. Some of their regulation have dual effect on cell fate under different pathological settings. Still, sirtuins mechanism has not been fully revealed, further studies are required to uncover the mysteries of sirtuins in the brain. Taken together, the apparent protective effects of sirtuins in neuron, astrocyte, microglia and Oligodendrocyte support that seven SIRT proteins synergistically regulated cell function via distinct mechanisms to enhance central nervous systerm homeostasis.
Author contributions
JY, XLT, ZQZ, JZ, and YLZ gathered data for the article, SYL and JY wrote the manuscript. ALL and SYL instructed the article’s content.
Funding
The present work was supported by grant from the National Natural Science Foundation of China (grant NO. 8197052076 to ALL, grant NO. 82171266 to JZ).This work was also supported by National Key R & and; D Program of China (No. 2020YFC2009002) and National Natural Science Foundation of China (81974160 and 81771159).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Abd El-Fatah I. M., Abdelrazek H. M. A., Ibrahim S. M., Abdallah D. M., El-Abhar H. S. (2021). Dimethyl fumarate abridged tauo-/amyloidopathy in a D-Galactose/ovariectomy-induced Alzheimer's-like disease: Modulation of AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3β, adiponectin/Adipo1R, and NF-κB/IL-1β/ROS trajectories. Neurochem. Int. 148, 105082. doi:10.1016/j.neuint.2021.105082
Almalki W. H., Alzahrani A., Mahmoud El-Daly M. E., Fadel Ahmed A. H. F. (2021). The emerging potential of SIRT-3 in oxidative stress-inflammatory axis associated increased neuroinflammatory component for metabolically impaired neural cell. Chem. Biol. Interact. 333, 109328. doi:10.1016/j.cbi.2020.109328
Aras E., Ramadori G., Kinouchi K., Liu Y., Ioris R. M., Brenachot X., et al. (2019). Light entrains diurnal changes in insulin sensitivity of skeletal muscle via ventromedial hypothalamic neurons. Cell Rep. 27 (8), 2385–2398. e2383. doi:10.1016/j.celrep.2019.04.093
Asher G., Gatfield D., Stratmann M., Reinke H., Dibner C., Kreppel F., et al. (2008). SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134 (2), 317–328. doi:10.1016/j.cell.2008.06.050
Bang M., Ryu O., Kim D. G., Mabunga D. F., Cho K. S., Kim Y., et al. (2019). Tenovin-1 induces senescence and decreases wound-healing activity in cultured rat primary astrocytes. Biomol. Ther. 27 (3), 283–289. doi:10.4062/biomolther.2018.107
Bao J., Zheng L., Zhang Q., Li X., Zhang X., Li Z., et al. (2016). Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microglia. Protein Cell 7 (6), 417–433. doi:10.1007/s13238-016-0269-2
Burg N., Bittner S., Ellwardt E. (2018). Role of the epigenetic factor Sirt7 in neuroinflammation and neurogenesis. Neurosci. Res. 131, 1–9. doi:10.1016/j.neures.2017.09.005
Cai H., Bian X., Chen L., Zhang N., Li L., Tang W., et al. (2021). Selective intra-arterial brain cooling induces cerebral protection against ischemia/reperfusion injury through SENP1-Sirt3 signaling. Free Radic. Biol. Med. 171, 272–283. doi:10.1016/j.freeradbiomed.2021.05.026
Cai Y., Xu L., Xu H., Fan X. (2016). SIRT1 and neural cell fate determination. Mol. Neurobiol. 53 (5), 2815–2825. doi:10.1007/s12035-015-9158-6
Cao R., Li S., Yin J., Guo L., Shi J. (2019). Sirtuin 3 promotes microglia migration by upregulating CX3CR1. Cell adh. Migr. 13 (1), 229–235. doi:10.1080/19336918.2019.1629224
Cardinale A., de Stefano M. C., Mollinari C., Racaniello M., Garaci E., Merlo D. (2015). Biochemical characterization of sirtuin 6 in the brain and its involvement in oxidative stress response. Neurochem. Res. 40 (1), 59–69. doi:10.1007/s11064-014-1465-1
Carloni S., Albertini M. C., Galluzzi L., Buonocore G., Proietti F., Balduini W. (2014). Melatonin reduces endoplasmic reticulum stress and preserves sirtuin 1 expression in neuronal cells of newborn rats after hypoxia-ischemia. J. Pineal Res. 57 (2), 192–199. doi:10.1111/jpi.12156
Chamberlain K. A., Huang N., Xie Y., LiCausi F., Li S., Li Y., et al. (2021). Oligodendrocytes enhance axonal energy metabolism by deacetylation of mitochondrial proteins through transcellular delivery of SIRT2. Neuron 109 (21), 3456–3472.e8. e3458. doi:10.1016/j.neuron.2021.08.011
Chaudhuri A. D., Yelamanchili S. V., Marcondes M. C., Fox H. S. (2013). Up-regulation of microRNA-142 in simian immunodeficiency virus encephalitis leads to repression of sirtuin1. FASEB J. official Publ. Fed. Am. Soc. Exp. Biol. 27 (9), 3720–3729. doi:10.1096/fj.13-232678
Chen H., Wu D., Ding X., Ying W. (2015). SIRT2 is required for lipopolysaccharide-induced activation of BV2 microglia. Neuroreport 26 (2), 88–93. doi:10.1097/WNR.0000000000000305
Chen H. Z., Guo S., Li Z. Z., Lu Y., Jiang D. S., Zhang R., et al. (2014). A critical role for interferon regulatory factor 9 in cerebral ischemic stroke. J. Neurosci. 34 (36), 11897–11912. doi:10.1523/JNEUROSCI.1545-14.2014
Chen T., Liu W. B., Qian X., Xie K. L., Wang Y. H. (2021). The AMPAR antagonist perampanel protects the neurovascular unit against traumatic injury via regulating Sirt3. CNS Neurosci. Ther. 27 (1), 134–144. doi:10.1111/cns.13580
Chen X., Wales P., Quinti L., Zuo F., Moniot S., Herisson F., et al. (2015). The sirtuin-2 inhibitor AK7 is neuroprotective in models of Parkinson's disease but not amyotrophic lateral sclerosis and cerebral ischemia. PloS one 10 (1), e0116919. doi:10.1371/journal.pone.0116919
Cheng A., Wang J., Ghena N., Zhao Q., Perone I., King T. M., et al. (2020). SIRT3 haploinsufficiency aggravates loss of GABAergic interneurons and neuronal network hyperexcitability in an alzheimer's disease model. J. Neurosci. 40 (3), 694–709. doi:10.1523/JNEUROSCI.1446-19.2019
Cheng Y., Takeuchi H., Sonobe Y., Jin S., Wang Y., Horiuchi H., et al. (2014). Sirtuin 1 attenuates oxidative stress via upregulation of superoxide dismutase 2 and catalase in astrocytes. J. Neuroimmunol. 269 (1-2), 38–43. doi:10.1016/j.jneuroim.2014.02.001
Cheng Y., Zeng X., Mai Q., Bai X., Jiang Y., Li J., et al. (2021). Insulin injections inhibits PTZ-induced mitochondrial dysfunction, oxidative stress and neurological deficits via the SIRT1/PGC-1α/SIRT3 pathway. Biochim. Biophys. Acta. Mol. Basis Dis. 1867 (6), 166124. doi:10.1016/j.bbadis.2021.166124
Cho S. H., Chen J. A., Sayed F., Ward M. E., Gao F., Nguyen T. A., et al. (2015). SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1β. J. Neurosci. 35 (2), 807–818. doi:10.1523/JNEUROSCI.2939-14.2015
Chong Z. Z., Maiese K. (2008). Enhanced tolerance against early and late apoptotic oxidative stress in mammalian neurons through nicotinamidase and sirtuin mediated pathways. Curr. Neurovasc. Res. 5 (3), 159–170. doi:10.2174/156720208785425666
Drews L., Zimmermann M., Westhoff P., Brilhaus D., Poss R. E., Bergmann L., et al. (2020). Ammonia inhibits energy metabolism in astrocytes in a rapid and glutamate dehydrogenase 2-dependent manner. Dis. Model. Mech. 13 (10), dmm047134. doi:10.1242/dmm.047134
Duangjan C., Rangsinth P., Zhang S., Wink M., Tencomnao T. (2021). Anacardium occidentale L. Leaf extracts protect against glutamate/H2O2-induced oxidative toxicity and induce neurite outgrowth: The involvement of SIRT1/nrf2 signaling pathway and teneurin 4 transmembrane protein. Front. Pharmacol. 12, 627738. doi:10.3389/fphar.2021.627738
Fang N., Cheng J., Zhang C., Chen K., Zhang C., Hu Z., et al. (2019). Sirt2 epigenetically down-regulates PDGFRα expression and promotes CG4 cell differentiation. Cell cycle 18 (10), 1095–1109. doi:10.1080/15384101.2019.1609818
Gomes B. A. Q., Silva J. P. B., Romeiro C. F. R., Dos Santos S. M., Rodrigues C. A., Goncalves P. R., et al. (2018). Neuroprotective mechanisms of resveratrol in alzheimer's disease: Role of SIRT1. Oxid. Med. Cell. Longev. 2018, 8152373. doi:10.1155/2018/8152373
Guo J., Zhang X. L., Bao Z. R., Yang X. K., Li L. S., Zi Y., et al. (2021). Gastrodin regulates the Notch signaling pathway and Sirt3 in activated microglia in cerebral hypoxic-ischemia neonatal rats and in activated BV-2 microglia. Neuromolecular Med. 23 (3), 348–362. doi:10.1007/s12017-020-08627-x
Hao W., Hao C., Wu C., Xu Y., Wu S., Lu X., et al. (2021). Aluminum impairs cognitive function by activating DDX3X-NLRP3-mediated pyroptosis signaling pathway. Food Chem. Toxicol. 157, 112591. doi:10.1016/j.fct.2021.112591
Har-Even M., Rubovitch V., Ratliff W. A., Richmond-Hacham B., Citron B. A., Pick C. G. (2021). Ketogenic Diet as a potential treatment for traumatic brain injury in mice. Sci. Rep. 11 (1), 23559. doi:10.1038/s41598-021-02849-0
Hardeland R. (2019). Aging, melatonin, and the pro- and anti-inflammatory networks. Int. J. Mol. Sci. 20 (5), E1223. doi:10.3390/ijms20051223
Hariharan N., Maejima Y., Nakae J., Paik J., Depinho R. A., Sadoshima J. (2010). Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes. Circ. Res. 107 (12), 1470–1482. doi:10.1161/CIRCRESAHA.110.227371
Harlan B. A., Killoy K. M., Pehar M., Liu L., Auwerx J., Vargas M. R. (2020). Evaluation of the NAD(+) biosynthetic pathway in ALS patients and effect of modulating NAD(+) levels in hSOD1-linked ALS mouse models. Exp. Neurol. 327, 113219. doi:10.1016/j.expneurol.2020.113219
He T., Shang J., Gao C., Guan X., Chen Y., Zhu L., et al. (2021). A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis. Acta Pharm. Sin. B 11 (3), 708–726. doi:10.1016/j.apsb.2020.11.002
Herskovits A. Z., Guarente L. (2014). SIRT1 in neurodevelopment and brain senescence. Neuron 81 (3), 471–483. doi:10.1016/j.neuron.2014.01.028
Hisahara S., Iwahara N., Matsushita T., Suzuki S., Matsumura A., Fujikura M., et al. (2021). SIRT1 decelerates morphological processing of oligodendrocyte cell lines and regulates the expression of cytoskeleton-related oligodendrocyte proteins. Biochem. Biophys. Res. Commun. 546, 7–14. doi:10.1016/j.bbrc.2021.01.095
Hu G., Liao K., Yang L., Pendyala G., Kook Y., Fox H. S., et al. (2017). Tat-mediated induction of miRs-34a & -138 promotes astrocytic activation via downregulation of SIRT1: Implications for aging in HAND. J. Neuroimmune Pharmacol. 12 (3), 420–432. doi:10.1007/s11481-017-9730-0
Jablonska B., Gierdalski M., Chew L. J., Hawley T., Catron M., Lichauco A., et al. (2016). Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury. Nat. Commun. 7, 13866. doi:10.1038/ncomms13866
Jeong J. K., Moon M. H., Lee Y. J., Seol J. W., Park S. Y. (2013). Autophagy induced by the class III histone deacetylase Sirt1 prevents prion peptide neurotoxicity. Neurobiol. Aging 34 (1), 146–156. doi:10.1016/j.neurobiolaging.2012.04.002
Jiang D. Q., Ma Y. J., Wang Y., Lu H. X., Mao S. H., Zhao S. H. (2019). Microglia activation induces oxidative injury and decreases SIRT3 expression in dopaminergic neuronal cells. J. Neural Transm. 126 (5), 559–568. doi:10.1007/s00702-019-02005-z
Jiao F., Wang Y., Zhang W., Zhang H., Chen Q., Wang L., et al. (2020). AGK2 alleviates lipopolysaccharide induced neuroinflammation through regulation of mitogen-activated protein kinase phosphatase-1. J. Neuroimmune Pharmacol. 15 (2), 196–208. doi:10.1007/s11481-019-09890-x
Khan M., Shah S. A., Kim M. O. (2018). 17β-Estradiol via SIRT1/acetyl-p53/NF-kB signaling pathway rescued postnatal rat brain against acute ethanol intoxication. Mol. Neurobiol. 55 (4), 3067–3078. doi:10.1007/s12035-017-0520-8
Kida Y., Goligorsky M. S. (2016). Sirtuins, cell senescence, and vascular aging. Can. J. Cardiol. 32 (5), 634–641. doi:10.1016/j.cjca.2015.11.022
Kim H., Kim S., Choi J. E., Han D., Koh S. M., Kim H. S., et al. (2019). Decreased neuron number and synaptic plasticity in SIRT3-knockout mice with poor remote memory. Neurochem. Res. 44 (3), 676–682. doi:10.1007/s11064-017-2417-3
Kong H., Wang H., Zhuo Z., Li Z., Tian P., Wu J., et al. (2020). Inhibition of miR-181a-5p reduces astrocyte and microglia activation and oxidative stress by activating SIRT1 in immature rats with epilepsy. Lab. Invest. 100 (9), 1223–1237. doi:10.1038/s41374-020-0444-1
Lee S., Jeon Y. M., Jo M., Kim H. J. (2021). Overexpression of SIRT3 suppresses oxidative stress-induced neurotoxicity and mitochondrial dysfunction in dopaminergic neuronal cells. Exp. Neurobiol. 30 (5), 341–355. doi:10.5607/en21021
Li D., Liu N., Zhao H. H., Zhang X., Kawano H., Liu L., et al. (2017). Interactions between Sirt1 and MAPKs regulate astrocyte activation induced by brain injury in vitro and in vivo. J. Neuroinflammation 14 (1), 67. doi:10.1186/s12974-017-0841-6
Li M., Li S. C., Dou B. K., Zou Y. X., Han H. Z., Liu D. X., et al. (2020). Cycloastragenol upregulates SIRT1 expression, attenuates apoptosis and suppresses neuroinflammation after brain ischemia. Acta Pharmacol. Sin. 41 (8), 1025–1032. doi:10.1038/s41401-020-0386-6
Li M., Meng N., Guo X., Niu X., Zhao Z., Wang W., et al. (2020). Dl-3-n-Butylphthalide promotes remyelination and suppresses inflammation by regulating AMPK/SIRT1 and STAT3/NF-κB signaling in chronic cerebral hypoperfusion. Front. Aging Neurosci. 12, 137. doi:10.3389/fnagi.2020.00137
Li M. Z., Zheng L. J., Shen J., Li X. Y., Zhang Q., Bai X., et al. (2018). SIRT1 facilitates amyloid beta peptide degradation by upregulating lysosome number in primary astrocytes. Neural Regen. Res. 13 (11), 2005–2013. doi:10.4103/1673-5374.239449
Li W., Zhang B., Tang J., Cao Q., Wu Y., Wu C., et al. (2007). Sirtuin 2, a mammalian homolog of yeast silent information regulator-2 longevity regulator, is an oligodendroglial protein that decelerates cell differentiation through deacetylating alpha-tubulin. J. Neurosci. 27 (10), 2606–2616. doi:10.1523/JNEUROSCI.4181-06.2007
Li Y., Hu K., Liang M., Yan Q., Huang M., Jin L., et al. (2021). Stilbene glycoside upregulates SIRT3/AMPK to promotes neuronal mitochondrial autophagy and inhibit apoptosis in ischemic stroke. Adv. Clin. Exp. Med. 30 (2), 139–146. doi:10.17219/acem/130608
Li Y., Jiao Q., Du X., Jiang H. (2020). Sirt1/FoxO1-Associated MAO-A upregulation promotes depressive-like behavior in transgenic mice expressing human A53T alpha-synuclein. ACS Chem. Neurosci. 11 (22), 3838–3848. doi:10.1021/acschemneuro.0c00628
Li Y., Liu T., Li Y., Han D., Hong J., Yang N., et al. (2020). Baicalin ameliorates cognitive impairment and protects microglia from LPS-induced neuroinflammation via the SIRT1/HMGB1 pathway. Oxid. Med. Cell. Longev. 2020, 4751349. doi:10.1155/2020/4751349
Li Y., Nie H., Wu D., Zhang J., Wei X., Ying W. (2013). Poly(ADP-ribose) polymerase mediates both cell death and ATP decreases in SIRT2 inhibitor AGK2-treated microglial BV2 cells. Neurosci. Lett. 544, 36–40. doi:10.1016/j.neulet.2013.03.032
Lin W., Qian X., Yang L. K., Zhu J., Wang D., Hang C. H., et al. (2021). Inhibition of miR-134-5p protects against kainic acid-induced excitotoxicity through Sirt3-mediated preservation of mitochondrial function. Epilepsy Res. 176, 106722. doi:10.1016/j.eplepsyres.2021.106722
Liu J., Jiao K., Zhou Q., Yang J., Yang K., Hu C., et al. (2021). Resveratrol alleviates 27-hydroxycholesterol-induced senescence in nerve cells and affects zebrafish locomotor behavior via activation of SIRT1-mediated STAT3 signaling. Oxid. Med. Cell. Longev. 2021, 6673343. doi:10.1155/2021/6673343
Liu M., Yang Y., Zhao B., Yang Y., Wang J., Shen K., et al. (2021). Exosomes derived from adipose-derived mesenchymal stem cells ameliorate radiation-induced brain injury by activating the SIRT1 pathway. Front. Cell Dev. Biol. 9, 693782. doi:10.3389/fcell.2021.693782
Liu M., Zhang X., Wang Y. (2021). Curcumin alleviates aβ42-induced neuronal metabolic dysfunction via the thrb/SIRT3 Axis and improves cognition in APPTG mice. Neurochem. Res. 46 (12), 3166–3178. doi:10.1007/s11064-021-03414-x
Liu Q., Fang J., Chen P., Die Y., Wang J., Liu Z., et al. (2019). Chicoric acid improves neuron survival against inflammation by promoting mitochondrial function and energy metabolism. Food Funct. 10 (9), 6157–6169. doi:10.1039/c9fo01417a
Liu Q., Sun Y. M., Huang H., Chen C., Wan J., Ma L. H., et al. (2021). Sirtuin 3 protects against anesthesia/surgery-induced cognitive decline in aged mice by suppressing hippocampal neuroinflammation. J. Neuroinflammation 18 (1), 41. doi:10.1186/s12974-021-02089-z
Liu S., Su Y., Sun B., Hao R., Pan S., Gao X., et al. (2020). Luteolin protects against CIRI, potentially via regulation of the SIRT3/AMPK/mTOR signaling pathway. Neurochem. Res. 45 (10), 2499–2515. doi:10.1007/s11064-020-03108-w
Liu Z., Sun Y., Qiao Q., Zhao T., Zhang W., Ren B., et al. (2017). Sesamol ameliorates high-fat and high-fructose induced cognitive defects via improving insulin signaling disruption in the central nervous system. Food Funct. 8 (2), 710–719. doi:10.1039/c6fo01562j
Luthi-Carter R., Taylor D. M., Pallos J., Lambert E., Amore A., Parker A., et al. (2010). SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc. Natl. Acad. Sci. U. S. A. 107 (17), 7927–7932. doi:10.1073/pnas.1002924107
Lv J., Tian J., Zheng G., Zhao J. (2017). Sirtuin7 is involved in protecting neurons against oxygen-glucose deprivation and reoxygenation-induced injury through regulation of the p53 signaling pathway. J. Biochem. Mol. Toxicol. 31 (10), e21955. doi:10.1002/jbt.21955
Ma L. H., Wan J., Yan J., Wang N., Liu Y. P., Wang H. B., et al. (2022). Hippocampal SIRT1-mediated synaptic plasticity and glutamatergic neuronal excitability are involved in prolonged cognitive dysfunction of neonatal rats exposed to propofol. Mol. Neurobiol. 59, 1938–1953. doi:10.1007/s12035-021-02684-4
Mao Q., Gong X., Zhou C., Tu Z., Zhao L., Wang L., et al. (2017). Up-regulation of SIRT6 in the hippocampus induced rats with depression-like behavior via the block Akt/GSK3β signaling pathway. Behav. Brain Res. 323, 38–46. doi:10.1016/j.bbr.2017.01.035
Meng J., Liu Y., Xie Z., Qing H., Lei P., Ni J. (2020). Nucleus distribution of cathepsin B in senescent microglia promotes brain aging through degradation of sirtuins. Neurobiol. Aging 96, 255–266. doi:10.1016/j.neurobiolaging.2020.09.001
Merlo S., Luaces J. P., Spampinato S. F., Toro-Urrego N., Caruso G. I., D'Amico F., et al. (2020). SIRT1 mediates melatonin's effects on microglial activation in hypoxia: In vitro and in vivo evidence. Biomolecules 10 (3), E364. doi:10.3390/biom10030364
Mojaverrostami S., Pasbakhsh P., Madadi S., Nekoonam S., Zarini D., Noori L., et al. (2020). Calorie restriction promotes remyelination in a Cuprizone-Induced demyelination mouse model of multiple sclerosis. Metab. Brain Dis. 35 (7), 1211–1224. doi:10.1007/s11011-020-00597-0
Munoz A., Correa C. L., Lopez-Lopez A., Costa-Besada M. A., Diaz-Ruiz C., Labandeira-Garcia J. L. (2018). Physical exercise improves aging-related changes in angiotensin, IGF-1, SIRT1, SIRT3, and VEGF in the substantia nigra. J. Gerontol. A Biol. Sci. Med. Sci. 73 (12), 1594–1601. doi:10.1093/gerona/gly072
Nicholatos J. W., Francisco A. B., Bender C. A., Yeh T., Lugay F. J., Salazar J. E., et al. (2018). Nicotine promotes neuron survival and partially protects from Parkinson's disease by suppressing SIRT6. Acta Neuropathol. Commun. 6 (1), 120. doi:10.1186/s40478-018-0625-y
Pais T. F., Szego E. M., Marques O., Miller-Fleming L., Antas P., Guerreiro P., et al. (2013). The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation. EMBO J. 32 (19), 2603–2616. doi:10.1038/emboj.2013.200
Pan S., Wu Y., Pei L., Li S., Song L., Xia H., et al. (2018). BML-111 reduces neuroinflammation and cognitive impairment in mice with sepsis via the SIRT1/NF-κB signaling pathway. Front. Cell. Neurosci. 12, 267. doi:10.3389/fncel.2018.00267
Panes J. D., Godoy P. A., Silva-Grecchi T., Celis M. T., Ramirez-Molina O., Gavilan J., et al. (2020). Changes in PGC-1α/SIRT1 signaling impact on mitochondrial homeostasis in amyloid-beta peptide toxicity model. Front. Pharmacol. 11, 709. doi:10.3389/fphar.2020.00709
Prozorovski T., Ingwersen J., Lukas D., Gottle P., Koop B., Graf J., et al. (2019). Regulation of sirtuin expression in autoimmune neuroinflammation: Induction of SIRT1 in oligodendrocyte progenitor cells. Neurosci. Lett. 704, 116–125. doi:10.1016/j.neulet.2019.04.007
Qin X., Chen J., Zhang G., Li C., Zhu J., Xue H., et al. (2020). Hydroxysafflor yellow A exerts anti-inflammatory effects mediated by SIRT1 in lipopolysaccharide-induced microglia activation. Front. Pharmacol. 11, 1315. doi:10.3389/fphar.2020.01315
Ramadori G., Fujikawa T., Anderson J., Berglund E. D., Frazao R., Michan S., et al. (2011). SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance. Cell Metab. 14 (3), 301–312. doi:10.1016/j.cmet.2011.06.014
Rangarajan P., Karthikeyan A., Lu J., Ling E. A., Dheen S. T. (2015). Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia. Neuroscience 311, 398–414. doi:10.1016/j.neuroscience.2015.10.048
Romeo-Guitart D., Leiva-Rodriguez T., Espinosa-Alcantud M., Sima N., Vaquero A., Dominguez-Martin H., et al. (2018). SIRT1 activation with neuroheal is neuroprotective but SIRT2 inhibition with AK7 is detrimental for disconnected motoneurons. Cell Death Dis. 9 (5), 531. doi:10.1038/s41419-018-0553-6
Scuderi C., Stecca C., Bronzuoli M. R., Rotili D., Valente S., Mai A., et al. (2014). Sirtuin modulators control reactive gliosis in an in vitro model of Alzheimer's disease. Front. Pharmacol. 5, 89. doi:10.3389/fphar.2014.00089
Shah S. A., Khan M., Jo M. H., Jo M. G., Amin F. U., Kim M. O. (2017). Melatonin stimulates the SIRT1/nrf2 signaling pathway counteracting lipopolysaccharide (LPS)-Induced oxidative stress to rescue postnatal rat brain. CNS Neurosci. Ther. 23 (1), 33–44. doi:10.1111/cns.12588
Shi Z., Li C., Yin Y., Yang Z., Xue H., Mu N., et al. (2018). Aerobic interval training regulated SIRT3 attenuates high-fat-diet-associated cognitive dysfunction. Biomed. Res. Int. 2018, 2708491. doi:10.1155/2018/2708491
Song W., Song Y., Kincaid B., Bossy B., Bossy-Wetzel E. (2013). Mutant SOD1G93A triggers mitochondrial fragmentation in spinal cord motor neurons: Neuroprotection by SIRT3 and PGC-1α. Neurobiol. Dis. 51, 72–81. doi:10.1016/j.nbd.2012.07.004
Stoyas C. A., Bushart D. D., Switonski P. M., Ward J. M., Alaghatta A., Tang M. B., et al. (2020). Nicotinamide pathway-dependent Sirt1 activation restores calcium homeostasis to achieve neuroprotection in spinocerebellar ataxia type 7. Neuron 105 (4), 630–644. doi:10.1016/j.neuron.2019.11.019
Tang X., Zhao Y., Zhou Z., Yan J., Zhou B., Chi X., et al. (2020). Resveratrol mitigates sevoflurane-induced neurotoxicity by the SIRT1-dependent regulation of BDNF expression in developing mice. Oxid. Med. Cell. Longev. 2020, 9018624. doi:10.1155/2020/9018624
Tang X. L., Wang X., Fang G., Zhao Y. L., Yan J., Zhou Z., et al. (2021). Resveratrol ameliorates sevoflurane-induced cognitive impairment by activating the SIRT1/NF-κB pathway in neonatal mice. J. Nutr. Biochem. 90, 108579. doi:10.1016/j.jnutbio.2020.108579
Tatomir A., Rao G., Boodhoo D., Vlaicu S. I., Beltrand A., Anselmo F., et al. (2020). Histone deacetylase SIRT1 mediates C5b-9-induced cell cycle in oligodendrocytes. Front. Immunol. 11, 619. doi:10.3389/fimmu.2020.00619
Thangaraj A., Chivero E. T., Tripathi A., Singh S., Niu F., Guo M. L., et al. (2021). HIV TAT-mediated microglial senescence: Role of SIRT3-dependent mitochondrial oxidative stress. Redox Biol. 40, 101843. doi:10.1016/j.redox.2020.101843
Tong Y., Fu H., Xia C., Song W., Li Y., Zhao J., et al. (2020). Astragalin exerted antidepressant-like action through SIRT1 signaling modulated NLRP3 inflammasome deactivation. ACS Chem. Neurosci. 11 (10), 1495–1503. doi:10.1021/acschemneuro.0c00156
Tyagi A., Mirita C., Shah I., Reddy P. H., Pugazhenthi S. (2021). Effects of lipotoxicity in brain microvascular endothelial cells during Sirt3 deficiency-potential role in comorbid alzheimer's disease. Front. Aging Neurosci. 13, 716616. doi:10.3389/fnagi.2021.716616
Wang S., Luo Q., Fan P. (2019). Cannabisin F from hemp (cannabis sativa) seed suppresses lipopolysaccharide-induced inflammatory responses in BV2 microglia as SIRT1 modulator. Int. J. Mol. Sci. 20 (3), E507. doi:10.3390/ijms20030507
Wang T., Wang Y., Liu L., Jiang Z., Li X., Tong R., et al. (2020). Research progress on sirtuins family members and cell senescence. Eur. J. Med. Chem. 193, 112207. doi:10.1016/j.ejmech.2020.112207
Wei H., Yin M., Lu Y., Yang Y., Li B., Liao X. X., et al. (2019). Mild hypothermia improves neurological outcome in mice after cardiopulmonary resuscitation through Silent Information Regulator 1-actviated autophagy. Cell Death Discov. 5, 129. doi:10.1038/s41420-019-0209-z
Wen Q., Wang Y., Pan Q., Tian R., Zhang D., Qin G., et al. (2021). MicroRNA-155-5p promotes neuroinflammation and central sensitization via inhibiting SIRT1 in a nitroglycerin-induced chronic migraine mouse model. J. Neuroinflammation 18 (1), 287. doi:10.1186/s12974-021-02342-5
Wu S., Wei Y., Li J., Bai Y., Yin P., Wang S. (2021). SIRT5 represses neurotrophic pathways and Aβ production in alzheimer's disease by targeting autophagy. ACS Chem. Neurosci. 12 (23), 4428–4437. doi:10.1021/acschemneuro.1c00468
Wu Z., Zhang Y., Zhang Y., Zhao P. (2020). Sirtuin 2 inhibition attenuates sevoflurane-induced learning and memory deficits in developing rats via modulating microglial activation. Cell. Mol. Neurobiol. 40 (3), 437–446. doi:10.1007/s10571-019-00746-9
Xie S., Jiang X., Doycheva D. M., Shi H., Jin P., Gao L., et al. (2021). Activation of GPR39 with TC-G 1008 attenuates neuroinflammation via SIRT1/PGC-1α/Nrf2 pathway post-neonatal hypoxic-ischemic injury in rats. J. Neuroinflammation 18 (1), 226. doi:10.1186/s12974-021-02289-7
Xu Y., Wan W. (2022). Acetylation in the regulation of autophagy. Autophagy, 1–9. doi:10.1080/15548627.2022.2062112
Yan J., Luo A., Gao J., Tang X., Zhao Y., Zhou B., et al. (2019). The role of SIRT1 in neuroinflammation and cognitive dysfunction in aged rats after anesthesia and surgery. Am. J. Transl. Res. 11 (3), 1555–1568.
Yan J., Luo A., Sun R., Tang X., Zhao Y., Zhang J., et al. (2020). Resveratrol mitigates hippocampal tau acetylation and cognitive deficit by activation SIRT1 in aged rats following anesthesia and surgery. Oxid. Med. Cell. Longev. 2020, 4635163. doi:10.1155/2020/4635163
Yang C., Wang W., Deng P., Li C., Zhao L., Gao H. (2021). Fibroblast growth factor 21 modulates microglial polarization that attenuates neurodegeneration in mice and cellular models of Parkinson's disease. Front. Aging Neurosci. 13, 778527. doi:10.3389/fnagi.2021.778527
Yang X., Geng K., Zhang J., Zhang Y., Shao J., Xia W. (2017). Sirt3 mediates the inhibitory effect of adjudin on astrocyte activation and glial scar formation following ischemic stroke. Front. Pharmacol. 8, 943. doi:10.3389/fphar.2017.00943
Yang Y., Zhang S., Guan J., Jiang Y., Zhang J., Luo L., et al. (2022). SIRT1 attenuates neuroinflammation by deacetylating HSPA4 in a mouse model of Parkinson's disease. Biochim. Biophys. Acta. Mol. Basis Dis. 1868 (5), 166365. doi:10.1016/j.bbadis.2022.166365
Yin X., Zhou Z., Qiu Y., Fan X., Zhao C., Bao J., et al. (2021). SIRT1 regulates tau expression and tau synaptic pathology. J. Alzheimers Dis. 84 (2), 895–904. doi:10.3233/JAD-215118
Yin Z., Geng X., Zhang Z., Wang Y., Gao X. (2021). Rhein relieves oxidative stress in an aβ1-42 oligomer-burdened neuron model by activating the SIRT1/PGC-1α-regulated mitochondrial biogenesis. Front. Pharmacol. 12, 746711. doi:10.3389/fphar.2021.746711
Yoon H., Kleven A., Paulsen A., Kleppe L., Wu J., Ying Z., et al. (2016). Interplay between exercise and dietary fat modulates myelinogenesis in the central nervous system. Biochim. Biophys. Acta 1862 (4), 545–555. doi:10.1016/j.bbadis.2016.01.019
Zhang D., Pan N., Jiang C., Hao M. (2021). LncRNA SNHG8 sponges miR-449c-5p and regulates the SIRT1/FoxO1 pathway to affect microglia activation and blood-brain barrier permeability in ischemic stroke. J. Leukoc. Biol. 111, 953–966. doi:10.1002/JLB.1A0421-217RR
Zhang X. H., Peng L., Zhang J., Dong Y. P., Wang C. J., Liu C., et al. (2020). Berberine ameliorates subarachnoid hemorrhage injury via induction of sirtuin 1 and inhibiting HMGB1/nf-κb pathway. Front. Pharmacol. 11, 1073. doi:10.3389/fphar.2020.01073
Zhang X. S., Lu Y., Li W., Tao T., Wang W. H., Gao S., et al. (2021). Cerebroprotection by dioscin after experimental subarachnoid haemorrhage via inhibiting NLRP3 inflammasome through SIRT1-dependent pathway Br. J. Pharmacol. 178 (18), 3648–3666. doi:10.1111/bph.15507
Zhang Y., Yang X., Ge X., Zhang F. (2019). Puerarin attenuates neurological deficits via Bcl-2/Bax/cleaved caspase-3 and Sirt3/SOD2 apoptotic pathways in subarachnoid hemorrhage mice. Biomed. Pharmacother. = Biomedecine Pharmacother. 109, 726–733. doi:10.1016/j.biopha.2018.10.161
Zhang Z., Bao X., Li D. (2021). Batroxobin inhibits astrocyte activation following nigrostriatal pathway injury. Neural Regen. Res. 16 (4), 721–726. doi:10.4103/1673-5374.295343
Zhang Z., Han K., Wang C., Sun C., Jia N. (2020). Dioscin protects against aβ1-42 oligomers-induced neurotoxicity via the function of SIRT3 and autophagy. Chem. Pharm. Bull. 68 (8), 717–725. doi:10.1248/cpb.c20-00046
Zhang Z., Li D., Xu L., Li H. P. (2019). Sirt1 improves functional recovery by regulating autophagy of astrocyte and neuron after brain injury. Brain Res. Bull. 150, 42–49. doi:10.1016/j.brainresbull.2019.05.005
Zhang Z., Zhang X., Wu X., Zhang Y., Lu J., Li D. (2022). Sirt1 attenuates astrocyte activation via modulating Dnajb1 and chaperone-mediated autophagy after closed head injury. Cereb. Cortex, bhac007. doi:10.1093/cercor/bhac007
Zhao H., Luo Y., Chen L., Zhang Z., Shen C., Li Y., et al. (2018). Sirt3 inhibits cerebral ischemia-reperfusion injury through normalizing Wnt/β-catenin pathway and blocking mitochondrial fission. Cell Stress Chaperones 23 (5), 1079–1092. doi:10.1007/s12192-018-0917-y
Zhao Y., Jiang Q., Zhang X., Zhu X., Dong X., Shen L., et al. (2021). l-Arginine alleviates LPS-induced oxidative stress and apoptosis via activating SIRT1-AKT-nrf2 and SIRT1-FOXO3a signaling pathways in C2C12 myotube cells. Antioxidants 10 (12), 1957. doi:10.3390/antiox10121957
Zhao Y., Luo P., Guo Q., Li S., Zhang L., Zhao M., et al. (2012). Interactions between SIRT1 and MAPK/ERK regulate neuronal apoptosis induced by traumatic brain injury in vitro and in vivo. Exp. Neurol. 237 (2), 489–498. doi:10.1016/j.expneurol.2012.07.004
Zhao Y., Zhang J., Zheng Y., Zhang Y., Zhang X. J., Wang H., et al. (2021). NAD+ improves cognitive function and reduces neuroinflammation by ameliorating mitochondrial damage and decreasing ROS production in chronic cerebral hypoperfusion models through Sirt1/PGC-1α pathway. J. Neuroinflammation 18 (1), 207. doi:10.1186/s12974-021-02250-8
Zheng R., Ruan Y., Yan Y., Lin Z., Xue N., Yan Y., et al. (2021). Melatonin attenuates neuroinflammation by down-regulating NLRP3 inflammasome via a SIRT1-dependent pathway in MPTP-induced models of Parkinson's disease. J. Inflamm. Res. 14, 3063–3075. doi:10.2147/JIR.S317672
Zhou B., Zhu Z., Ransom B. R., Tong X. (2021). Oligodendrocyte lineage cells and depression. Mol. Psychiatry 26 (1), 103–117. doi:10.1038/s41380-020-00930-0
Zhou D., Jiang Y. (2019). Sirtuin 3 attenuates neuroinflammation-induced apoptosis in BV-2 microglia. Aging (Albany NY) 11 (20), 9075–9089. doi:10.18632/aging.102375
Zhou J., Li X. Y., Liu Y. J., Feng J., Wu Y., Shen H. M., et al. (2022). Full-coverage regulations of autophagy by ROS: From induction to maturation. Autophagy 18 (6), 1240–1255. doi:10.1080/15548627.2021.1984656
Zhou Y., Peng L., Li Y., Zhao Y. (2022). Silent information regulator 1 ameliorates oxidative stress injury via PGC-1α/PPARγ-Nrf2 pathway after ischemic stroke in rat. Brain Res. Bull. 178, 37–48. doi:10.1016/j.brainresbull.2021.11.001
Zhu Z., Li H., Chen W., Cui Y., Huang A., Qi X. (2020). Perindopril improves cardiac function by enhancing the expression of SIRT3 and PGC-1α in a rat model of isoproterenol-induced cardiomyopathy. Front. Pharmacol. 11, 94. doi:10.3389/fphar.2020.00094
Keywords: sirtuins, central nervous syste, neuron, microglia, astrocyte, oligodendrocyte
Citation: Yan J, Tang X, Zhou Z-q, Zhang J, Zhao Y, Li S and Luo A (2022) Sirtuins functions in central nervous system cells under neurological disorders. Front. Physiol. 13:886087. doi: 10.3389/fphys.2022.886087
Received: 28 February 2022; Accepted: 25 July 2022;
Published: 30 August 2022.
Edited by:
Dariusz Szukiewicz, Medical University of Warsaw, PolandReviewed by:
Miguel Perez-Pinzon, University of Miami, United StateJames Howard Eubanks, University Health Network, Canada
Copyright © 2022 Yan, Tang, Zhou, Zhang, Zhao, Li and Luo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Shiyong Li, c2hpeW9uZ2xpQGh1c3QuZWR1LmNu; Ailin Luo, YWxsdW9AaHVzdC5lZHUuY24=