Microglial P2Y12 receptor is a key regulator of neuroimmune homeostasis, but its role in integrating sleep, glymphatic influx, and microglial dynamics across sexes remains to be further investigated. In this study, we employed the P2Y12 antagonist MRS2395 for pharmacological inhibition in adult male and female C57BL/6 J mice. We assessed glymphatic influx, microglial density and morphology across multiple brain regions, sleep architecture via EEG, and behavioral outcomes. P2Y12 blockade disrupted sleep-stage glymphatic influx, microglial parameters, and sleep architecture, with the greater effects observed in females, particularly a greater suppression of glymphatic influx during sleep and more severe sleep fragmentation, characterized by increased state transitions and altered spectral power. In both sexes, P2Y12 inhibition reduced microglial branching complexity. Locomotor activity, cognitive performance, and anxiety-like behaviors did not differ significantly between the two sexes. These results preliminarily suggest that the microglial P2Y12 receptor pathway exerts sex-differential effects on glymphatic influx and sleep architecture during the rest phase, behavioral effects occurred but did not significantly differ between sexes in the short term.

Background Chronic cerebral hypoperfusion-induced white matter lesions are a major contributor to vascular cognitive impairment in aging, characterized by microglial activation and defective clearance of cholesterol-rich myelin debris. Perilipin-2 (PLIN2), a key lipid droplet (LD)-associated protein involved in myelin metabolism, has an undefined role in ischemic white matter injury. Methods Microglia-specific Plin2 knockout ( Plin2 ⁻/⁻ ) mice were subjected to bilateral common carotid artery stenosis (BCAS) to model cerebral hypoperfusion. Cognitive function, white matter integrity, and microglial phenotype were assessed. In parallel, integrated microglial transcriptomic and lipidomic analyses were performed to characterize inflammatory states and lipid metabolic profiles. Furthermore, the autophagy inhibitor chloroquine (CQ) was used in vivo and in vitro to test mechanistic dependence on autophagy. Results Plin2 deletion rescued BCAS-induced cognitive and motor deficits, attenuated white matter damage, and promoted remyelination. Plin2 ⁻/⁻ microglia exhibited enhanced clearance of myelin-derived LDs and a reduced pro-inflammatory state, driven by an upregulation of the autophagy-lysosomal pathway (lipophagy). Crucially, CQ treatment abolished these neuroprotective effects, as evidenced by re-induced LD accumulation, and reinstated inflammatory activation in Plin2 ⁻/⁻ mice and cultured microglia. Conclusion Microglial Plin2 deletion protects against hypoperfusion injury by enhancing LD clearance, reprogramming lipid metabolism, and suppressing neuroinflammation in an autophagy-dependent manner. Clinically, PLIN2 may represent a promising therapeutic target for ischemic white matter injury and vascular cognitive impairment.

The mitochondrial dysfunction is usually associated with the pathogenesis of Parkinson's disease (PD) and serves as a potential therapeutic target for PD. The viscosity is a specific biomarker of PD and reflects the condition of subcellular organelle. Therefore, imaging mitochondrial viscosity is essential for understanding pathophysiological processes of PD. Herein, a near-infrared (NIR) emissive carbon dot (CD), named as oA-5, is rationally designed based on oxazine groups to emulate the microenvironment-sensitive behavior of benzophenoxazine fluorophores for viscosity response. Meanwhile, 2-aminophenol is adopted as the other carbon source, which is polymerized with the oxazine groups, to further enhance the sensitivity towards viscosity and facilitate accumulation in mitochondria. Besides, the localization of oA-5 to the mitochondria is independent on mitochondrial membrane potentials. Particularly, the oA-5 exhibits satisfactory blood-brain-barrier penetration ability and deposits in prefrontal cortex, striatum, hippocampus and substantia nigra regions. Thus, it is successful as a fluorescence probe to monitor the mitochondrial viscosity in living PD cells and mice. Based on this probe, an anti-PD drug evaluating platform is established, and epigallocatechin gallate is found to be the most effective among the studied natural polyphenols. The present study offers a feasible method to construct the NIR fluorescence CDs for visualizing mitochondrial viscosity in living cells and mice, and evaluating the drug therapeutic efficacy against PD, which would provide a useful tool for the fundamental researches and drug development of PD.

Excessive reactive oxygen species (ROS) accumulation and dysregulated inflammation drive acetaminophen (APAP)-induced acute liver injury (ALI), yet the therapeutic effect of the commonly used clinical drug N-acetylcysteine (NAC) still has certain limitations at present. Here, we engineered a multifunctional nanozyme nanocomposite, MPCNH, by in situ deposition of bimetallic PtCu nanoparticles onto UiO-66 metal-organic frameworks (MOFs), loading NAC, and coating with hyaluronic acid (HA) to enhance biocompatibility. MPCNH exhibited cascade superoxide dismutase (SOD)-like and catalase (CAT)-like catalytic activities, enabling rapid ROS clearance and mitochondrial protection in APAP-challenged hepatocytes. Meanwhile, the delivery of the therapeutic drug NAC was achieved. In vivo, MPCNH lowered serum transaminases, activated the Keap1-Nrf2 antioxidant pathway, shifted macrophages polarization toward an anti-inflammatory M2 phenotype and restored metabolic balance. By integrating catalytic and pharmacological functions, MPCNH offers a synergistic strategy to simultaneously eliminate oxidative stress and regulate inflammation, providing a promising therapeutic platform for oxidative stress-driven liver injury.

Neuroinflammation plays a pivotal role in the pathogenesis of secondary brain injury (SBI) after intracerebral hemorrhage (ICH). TREK-1 is a background potassium channel, and its role in regulating neuroinflammation after ICH remains unclear. In this study, ICH models were induced in wide-type (WT) and TREK knockout mice via intra-striatal administration of collagenase. Additionally, WT ICH mice were treated with the TREK-1 agonist ML67-33. Immunofluorescence, western blot, quantitative real-time PCR, enzyme-linked immunosorbent assay, and RNA-sequencing were performed to determine the role and the mechanism of TREK-1 in regulating neuroinflammation after ICH. The results indicate that TREK-1 deficiency exacerbated microglia/macrophages activation and pro-inflammatory polarization, as well as the influx of inflammatory cytokines and peripheral inflammatory cells compared to WT ICH mice. Conversely, activation of TREK-1 attenuated the inflammatory response and SBI post-ICH. These effects may be mediated through the CX3CL1-CX3CR1 pathway, as validated by specific inhibitors AZD8797. This study identified TREK-1 as a crucial modulator in alleviating SBI by regulating the inflammatory microenvironment via the CX3CL1-CX3CR1 pathway.

The detection and imaging of alpha-synuclein fibrils (alpha-syn-F) is vital for pathological research and drug development of Parkinson's disease. Herein, a red emissive fluorescent carbon dot (CD) with solvatochromism, named as NB- 12, is designed with Nile blue and L-tryptophan as the carbon source. The density functional theory calculations are performed to understand the effect of nitrogen content on fluorescent property of CDs. The turn-on fluorescence of NB-12 is observed upon the interaction with the alpha-syn-F but not towards its monomer. The detection limit of NB-12 towards alpha-syn-F can reach as low as 9.5 nM. This high sensitivity is due to the wavelength blueshift of NB-12 towards fibrils to reduce the self-background of the probe and enhance the signal-to-noise ratio. Moreover, the fluorescence wavelength shift and intensity variation of NB-12 can be employed to establish dual-element fluorescence array but by one probe to distinguish individual amyloid fibrils as well as the protein mixture with high accuracy. Additionally, NB-12 has succeeded in imaging alpha-syn-F in brain slices of A53T mice and NL-5901 C. elegans. The present study offers a feasible method to construct the fluorescent CDs with solvatochromism for multi-mode detection of alpha-syn-F in vitro, ex vitro and in vivo.

Wound healing is a dynamic process often accompanied by bacterial infection. Bacterial proliferation and induced excessive inflammation hinder the healing process in infectious wounds, leading to refractory wounds. Addressing the challenges of infectious wounds requires the development of multifunctional dressings capable of eliminating bacterial infection, relieving inflammation, and restoring the wound microenvironment. In this study, a Ag+-ion functionalized and a Cu2+-ion functionalized UiO-67 metal-organic framework (MOF-Ag and MOF-Cu) are incorporated into an oxidized dextran and gelatin mixture to fabricate hydrogel, termed as OGAC. The resulting OGAC exhibited injectable, adhesive, hemostatic, antibacterial, and anti-inflammatory properties, along with good biocompatibility. The OGAC hydrogel precursor could be injected in situ at the wound site to cover the wound, serving as a physical barrier to protect wounds. Moreover, the OGAC demonstrates efficient antibacterial and anti-biofilm activity, against both Escherichia coli and Staphylococcus aureus. Additionally, OGAC has superoxide dismutase-like and glutathione peroxidase-like activity for anti-oxidation, which is conducive to reduce inflammation in the wound. The OGAC reveals high performance for infected wound healing in a mouse model. These findings suggest that OGAC is a promising candidate with multiple functionalities for clinical wound management.

Microglia are major resident immune cells in the central nervous system and are actively involved in the pathogenesis of ischemic stroke. Histone lactylation confers macrophage homeostatic gene expressions and regulates physiological and immune-related pathological conditions. However, the spatiotemporal expression and functional role of histone lactylation in microglial reprogramming and neurological injuries after ischemic stroke remain elusive. In this study, we observed increased levels of histone lactylation in peri-infarct areas after the middle cerebral artery occlusion-induced focal cerebral ischemia in mice. The enhanced histone lactylation favored an anti-inflammatory micro-environment and provided neuroprotective effects after ischemia, which might be mediated by histone H3 lysine 18 lactylation (H3K18la)-regulated plxnb2 expression in microglia. Microglia-specific inhibition of plxnb2 abrogated the neuroprotective effects of lactate after ischemic stroke. These findings suggest that interventions aimed at the lactate/lactylation(H3K18la)/plxnb2 axis may represent a promising therapeutic strategy for ischemic stroke treatment.

Ischemic stroke (IS) remains a leading cause of mortality and long-term disability worldwide, with limited therapeutic options available. Inflammation and oxidative stress play key roles in the poor prognosis of IS. By designing a three-dimensional architecture based on the alignment of different nanoparticles, we develop a builtin, multienzyme-mimicking Pt/polydopamine (PNP) nano-hybrid for the rapid and sustained treatment of IS, eliminating the need for the frequent administrations required by traditional therapies. PNP shares the catalytic feature of both CAT and SOD enzymes to scavenge reactive oxygen species (ROS) originating from the built-in Pt nanoparticles and inherits anti-inflammatory capability from polydopamine nano-substrate. Compared to natural enzymes, PNP exhibits greater stability and tolerance to external conditions, including a wide range of temperatures and pH levels. To explore the effects of PNP on IS and elucidate its underlying mechanisms, we establish both in vivo and in vitro models to simulate IS, including the transient middle cerebral artery occlusion (tMCAO) mouse model and cellular oxygen-glucose deprivation-reperfusion (OGD/R) model. Experimental results show that PNP can cross the blood-brain barrier, accumulate in ischemic lesions, and alleviate both acute and chronic neuroinflammation and oxidative stress post-IS. This leads to a marked reduction in infarct volume and neuronal apoptosis, alongside substantial improvements in neurological function following IS. Furthermore, PNP effectively modulates the activation and promotes the anti-inflammatory polarization of microglia in ischemic lesions, further contributing to therapeutic efficacy. These effects of PNP persist for over 35 days, supporting long-term recovery. As a result, PNP treatment significantly enhances the survival and alleviates cerebral atrophy of mice after IS. PNP shows great promise as a neuroprotective treatment to enhance sustained neurological outcomes following IS.

BACKGROUND:Chronic cerebral hypoperfusion-induced white matter lesions are an important cause of vascular cognitive impairment in aging life. TGF-β1 (transforming growth factor β1) is widely recognized as a multifunctional cytokine participating in numerous pathophysiological processes in the central nervous system. In this study, we aimed to evaluate the neuroprotective potentials of TGF-β1 in ischemic white matter lesions. METHODS:A mouse model of bilateral common carotid artery stenosis was established to imitate the ischemic white matter lesions. The agonist of the TGF-β1 pathway was continuously applied via intraperitoneal injection. The Morris water maze test and gait analysis system were used to assess the cognitive and gait disorders in modeling mice. The Luxol fast blue staining, immunofluorescence, and electron microscopy were conducted to determine the severity of demyelinating lesions, microglial activation, and dysfunction of the autophagy-lysosomal pathway in microglia. Furthermore, primary cultured microglia were exposed to extracted myelin debris and TGF-β1 in vitro to explore the underlying mechanisms. RESULTS:As evaluated by behavioral tests, TGF-β1 significantly alleviated the cognitive dysfunction and gait disorder in bilateral common carotid artery stenosis-modeling mice. The demyelinating lesion and remyelination process were also found to be highly improved by activation of the TGF-β1 pathway. The results of immunostaining and electron microscopy showed that TGF-β1 could ameliorate microglial activation and the dysfunction of lipid metabolism in myelin-engulfed microglia. Mechanistically, in primary cultured microglia exposed to myelin debris, administration of TGF-β1 notably mitigated the inflammatory response and accumulation of intracellular lipid droplets via promoting the lipid droplets degradation in the autophagy-lysosomal pathway, as quantified by flow cytometry, immunostaining, Western blot, etc. Yet, the application of autophagy inhibitor 3-methyladenine significantly reversed the above anti-inflammatory effects of TGF-β1. CONCLUSIONS:TGF-β1 relieved cognitive deficit, demyelinating lesions, and microglia-mediated neuroinflammation in bilateral common carotid artery stenosis modeling by reducing abnormal lipid droplet accumulation and dysfunction of the autophagy-lysosomal pathway in microglia. Clinically, staged activation of the TGF-β1 pathway may become a potential target and promising treatment for ischemic white matter lesions and vascular cognitive impairment.

Brain takes up approximately 20% of the total body oxygen and glucose consumption due to its relatively high energy demand. Glucose is one of the major sources to generate ATP, the process of which can be realized via glycolysis, oxidative phosphorylation, pentose phosphate pathways and others. Lactate serves as a hub molecule amid these metabolic pathways, as it may function as product of glycolysis, substrate of a variety of enzymes and signal molecule. Thus, the roles of lactate in central nervous system (CNS) diseases need to be comprehensively elucidated. Histone lactylation is a novel lactate-dependent epigenetic modification that plays an important role in immune regulation and maintaining homeostasis. However, there's still a lack of studies unveiling the functions of histone lactylation in the CNS. In this review, we first comprehensively reviewed the roles lactate plays in the CNS under both physiological and pathological conditions. Subsequently, we've further discussed the functions of histone lactylation in various neurological diseases. Furthermore, future perspectives regarding histone lactylation and its therapeutic potentials in stroke are also elucidated, which may possess potential clinical applications.

Soluble epoxide hydrolase (sEH) inhibition has been shown multiple beneficial effects against brain injuries of Intracerebral hemorrhage (ICH). However, the underlying mechanism of its neuroprotective effects after ICH has not been explained fully. Ferroptosis, a new form of iron-dependent programmed cell death, has been shown to be implicated in the secondary injuries after ICH. In this study, We examined whether sEH inhibition can alleviate brain injuries of ICH through inhibiting ferroptosis. Expression of several markers for ferroptosis was observed in the peri-hematomal brain tissues in mice after ICH. lip-1, a ferroptosis inhibitor, alleviated iron accumulation, lipid peroxidation and the secondary damages post-ICH in mice model. Intraperitoneal injection of 1-Trifluoromethoxyphenyl-3- (1-propionylpiperidin-4-yl)urea (TPPU), a highly selective sEH inhibitor, could inhibit ferroptosis and alleviate brain damages in ICH mice. Furthermore, RNA-sequencing was applied to explore the potential regulatory mechanism underlying the effects of TPPU in ferroptosis after ICH. C-C chemokine ligand 5 (CCL5) may be the key factor by which TPPU regulated ferroptosis after ICH since CCL5 antagonist could mimic the effects of TPPU and CCL5 reversed the inhibitive effect of TPPU on ferroptosis and the neuroprotective effects of TPPU on secondary damage after ICH. Taken together, these data indicate that ferroptosis is a key pathological feature of ICH and Soluble epoxide hydrolase inhibitor can exert neuroprotective effect by preventing ferroptosis after ICH.

Demyelination occurs in multiple central nervous system (CNS) disorders and is tightly associated with neuroinflammation. Pyroptosis is a form of pro-inflammatory and lytic cell death which has been observed in CNS diseases recently. Regulatory T cells (Tregs) have exhibited immunoregulatory and protective effects in CNS diseases. However, the roles of Tregs in pyroptosis and their involvement in LPC-induced demyelination have not been explicated. In our study, Foxp3-diphtheria toxin receptor (DTR) mice treated with diphtheria toxin (DT) or PBS were subjected to two-site lysophosphatidylcholine (LPC) injection. Immunofluorescence, western blot, Luxol fast blue (LFB) staining, quantitative real-time PCR (qRT-PCR) and neurobehavior assessments were performed to evaluate the severity of demyelination, neuroinflammation and pyroptosis. Pyroptosis inhibitor was further used to investigate the role of pyroptosis in LPC-induced demyelination. RNA-sequencing was applied to explore the potential regulatory mechanism underlying the involvement of Tregs in LPC-induced demyelination and pyroptosis. Our results showed that depletion of Tregs aggravated microgliosis, inflammatory responses, immune cells infiltration and led to exacerbated myelin injury as well as cognitive defects in LPC-induced demyelination. Microglial pyroptosis was observed after LPC-induced demyelination, which was aggravated by Tregs depletion. Inhibition of pyroptosis by VX765 reversed myelin injury and cognitive function exacerbated by Tregs depletion. RNA-sequencing showed TLR4/myeloid differentiation marker 88 (MyD88) as the central molecules in Tregs-pyroptosis pathway, and refraining TLR4/MyD88/NF-κB pathway alleviated the aggravated pyroptosis induced by Tregs depletion. In conclusion, our findings for the first time indicate that Tregs alleviate myelin loss and improve cognitive function by inhibiting pyroptosis in microglia via TLR4/MyD88/NF-κB pathway in LPC-induced demyelination.

缺血性脑卒中是一种急性中枢神经系统疾病,发病率、致死率、致残率居高不下,给患者家庭和社会带来了极大负担.缺血性脑卒中病理机制复杂,治疗手段有限,亟需进一步探索病理机制及新的治疗靶点.既往中性粒细胞在缺血性脑卒中的作用长期被忽视,但近十年的研究提示中性粒细胞活跃参与了缺血性脑卒中后神经损伤与修复过程.同时,中性粒细胞胞外陷阱(neutrophil extracellular traps,NETs)作为中性粒细胞的一种新的调控机制,在缺血性脑卒中后急性炎症、血栓形成、血管损害等病理过程中发挥重要作用,可能是促进缺血性脑卒中后新生血管和功能恢复的关键.本文重点评述了中性粒细胞特别是NETs在缺血性脑卒中神经损伤与修复中的作用以及靶向中性粒细胞和NETs治疗的相关进展.

The redox-active metal ions, especially Cu2+, are highly correlated to Alzheimer's disease (AD) by causing metal ion-mediated oxidative stress and toxic metal-bound β-amyloid (Aβ) aggregates. Numerous pieces of evidence have revealed that the regulation of metal homeostasis could be an effective therapeutic strategy for AD. Herein, in virtue of the interaction of both amino-containing silane and ethylenediaminetetraacetic acid disodium salt for Cu2+, the silicon-carbon dots (SiCDs) are deliberately prepared using these two raw materials as the cocarbon source; meanwhile, to realize the local enrichment of SiCDs and further maximize the chelating ability to Cu2+, the SiCDs are feasibly loaded to the biocompatible mesoporous silica nanoparticles (mSiO2) with the interaction between residual silane groups on SiCDs and silanol groups of mSiO2. Thus-obtained nanocomposites (i.e., mSiO2@SiCDs) could serve as an efficient Cu2+ chelator with satisfactory metal selectivity and further modulate the enzymic activity of free Cu2+ and the Aβ42-Cu2+ complex to alleviate the pathological oxidative stress with an anti-inflammatory effect. Besides, mSiO2@SiCDs show an inspiring inhibitory effect on Cu2+-mediated Aβ aggregation and further protect the neural cells against the toxic Aβ42-Cu2+ complex. Moreover, the transgenic Caenorhabditis elegans CL2120 assay demonstrates the protective efficacy of mSiO2@SiCDs on Cu2+-mediated Aβ toxicity in vivo, indicating its potential for AD treatment.

Objective Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that leads to severe disability. A large proportion of NMOSD patients are seropositive for aquaporin‐4 autoantibodies (AQP4‐IgG, named as NMO‐IgG) targeting AQP4, which is selectively expressed on astrocytes in the central nervous system. This study tests the hypothesis that in response to NMO‐IgG, the pathogenic astrocyte‐derived exosomes are released and injure the neighboring cells. Methods IgG purified from serum of either NMOSD patients or healthy controls was used to generate astrocyte‐derived exosomes (AST‐Exos NMO vs AST‐Exos CON ) in cultured rat astrocytes. The exosomes were respectively delivered to cultured rat oligodendrocytes in vitro, tissue culture of rat optic nerve ex vivo, and rat optic nerve in vivo to evaluate the pathogenic roles of AST‐Exos NMO . The microRNA (miRNA) sequencing of AST‐Exos and verification were performed to identify the key pathogenic miRNA. The custom‐designed adeno‐associated virus (AAV) antagonizing the key miRNA was evaluated for its therapeutic effects in vivo. Moreover, the serum levels of the key exosomal miRNA were measured between NMOSD patients and healthy controls. Results AST‐Exos NMO led to notable demyelination in both cultured oligodendrocytes and optic nerve tissue. Exosomal miR‐129‐2‐3p was identified as the key miRNA mediating the demyelinating pathogenesis via downstream target gene SMAD3 . AAV antagonizing miR‐129‐2‐3p protected against demyelination in an NMOSD rodent model. The serum exosomal miR‐129‐2‐3p level was significantly elevated in NMOSD patients and correlated with disease severity. Interpretation Astrocytes targeted by NMO‐IgG release pathogenic exosomes that could potentially be used as therapeutic targets or disease monitoring biomarkers in NMOSD. ANN NEUROL 2023;94:163–181

Depression is a common neuropsychiatric disorder with high incidence and disability. Electroacupuncture (EA) is effective in the treatment of depression. However, the underlying mechanisms are not fully understood. Social isolation stress during post-weaning period can impair purinergic signaling in the brain of rodents and has emerged as a major risk factor for depression. The purpose of this study was to investigate the involvement of P2Y1 receptor (P2Y1R) in the antidepressant-like effects of EA. In this study, C57BL/6 mice were randomly assigned to group-housed (GH) or social isolated (SI) groups at post-natal day 21. After 6 weeks of social isolation, EA was performed on acupoints “Bai-hui” (GV20) and “Yin-tang” (GV29), or non-acupoints for 4 weeks. The SI mice received either intracerebroventricular injection of a selective P2Y1R agonist, MRS2365 (1 nmol); or a selective P2Y1R antagonist, MRS2179 (2 μmol), before and after EA. We found that SI mice exhibited depression-like behaviors accompanied with anxiety-like behaviors. The expressions of P2Y1R were well co-localized with GFAP-positive astrocytes and increased in the prefrontal cortex and hippocampus of SI mice. After treated with MRS2179, the depression-like behaviors of SI mice were attenuated, but not with MRS2365. Meanwhile, we found that EA could attenuate social isolation caused depression- and anxiety-like behaviors, and inhibited the up-regulation of P2Y1R in the prefrontal cortex and hippocampus of SI mice. Notably, the positive effects of EA on depression-like behaviors of SI mice could be reversed by MRS2365, while MRS2365 had no effect on the anxiolytic-like effects of EA. Therefore, we provide new evidence that EA could ameliorate depression- and anxiety-like behaviors in social isolation stress mice, and P2Y1R was involved in the antidepressant-like effects of EA.

The concept of the glial-vascular unit (GVU) was raised recently to emphasize the close associations between brain cells and cerebral vessels, and their coordinated reactions to diverse neurological insults from a “glio-centric” view. GVU is a multicellular structure composed of glial cells, perivascular cells, and perivascular space. Each component is closely linked, collectively forming the GVU. The central roles of glial and perivascular cells and their multi-level interconnections in the GVU under normal conditions and in central nervous system (CNS) disorders have not been elucidated in detail. Here, we comprehensively review the intensive interactions between glial cells and perivascular cells in the niche of perivascular space, which take part in the modulation of cerebral blood flow and angiogenesis, formation of the blood-brain barrier, and clearance of neurotoxic wastes. Next, we discuss dysfunctions of the GVU in various neurological diseases, including ischemic stroke, spinal cord injury, Alzheimer’s disease, and major depression disorder. In addition, we highlight the possible therapies targeting the GVU, which may have potential clinical applications.

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Vascular cognitive impairment is the second most common cause of dementia which can be induced by chronic cerebral hypoperfusion. Regulatory T cells (Tregs) have been proven to provide beneficial effects in several central nervous system (CNS) diseases, but the roles of Tregs in chronic cerebral hypoperfusion-induced white matter damage have not been explored. In this study, Foxp3-diphtheria toxin receptor (DTR) mice treated with diphtheria toxin (DT) and wild type C57BL/6 mice treated with anti-CD25 antibody were subjected to bilateral carotid artery stenosis (BCAS). Flow cytometry analysis showed Tregs were widely distributed in spleen whereas barely distributed in brain under normal conditions. The distribution of lymphocytes and Tregs did not change significantly in spleen and brain after BCAS. Depletion of Tregs decreased the numbers of mature oligodendrocytes and anti-inflammatory microglia at 14 days and 28 days following BCAS. And pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and interferon-γ (IFN-γ) showed higher expression after Tregs depletion. In contrast, Tregs depletion did not change the overall severity of white matter injury as shown by the expression of myelin-associated glycoprotein (MAG), myelin basic protein (MBP), luxol fast blue (LFB) staining and electron microscopy assay. Moreover, Tregs depletion had marginal effect on cognition defects after BCAS revealed by Morris water maze and novel object recognition examination at 28 days after BCAS. In summary, our results suggest an anti-inflammatory role of Tregs with marginal effects on white matter damage in mice after BCAS-induced chronic cerebral hypoperfusion.