Myelin Oligodendrocyte Glycoprotein-IgG Contributes to Oligodendrocytopathy in the Presence of Complement, Distinct from Astrocytopathy Induced by AQP4-IgG

Immunoglobulin G against myelin oligodendrocyte glycoprotein(MOG-Ig G) is detectable in neuromyelitis optica spectrum disorder(NMOSD) without aquaporin-4 Ig G(AQP4-Ig G), but its pathogenicity remains unclear.In this study, we explored the pathogenic mechanisms of MOG-Ig G in vitro and in vivo and compared them with those of AQP4-Ig G. MOG-Ig G-positive serum induced complement activation and cell death in human embryonic kidney(HEK)-293 T cells transfected with human MOG. In C57 BL/6 mice and Sprague-Dawley rats, MOG-Ig G only caused lesions in the presence of complement. Interestingly, AQP4-Ig G induced astroglial damage, while MOGIg G mainly caused myelin loss. MOG-Ig G also induced astrocyte damage in mouse brains in the presence ofcomplement. Importantly, we also observed ultrastructural changes induced by MOG-Ig G and AQP4-Ig G. These findings suggest that MOG-Ig G directly mediates cell death by activating complement in vitro and producing NMOSDlike lesions in vivo. AQP4-Ig G directly targets astrocytes,while MOG-Ig G mainly damages oligodendrocytes.

Human umbilical cord Wharton's jelly-derived oligodendrocyte precursor-like cells for axon and myelin sheath regeneration

Human umbilical mesenchymal stem cells from Wharton＇s jelly of the umbilical cord were induced to differentiate into oligodendrocyte precursor-like cells in vitro. Oligodendrocyte precursor cells were transplanted into contused rat spinal cords. Immunofluorescence double staining indicated that transplanted cells survived in injured spinal cord, and differentiated into mature and immature oligodendrocyte precursor cells. Biotinylated dextran amine tracing results showed that cell transplantation promoted a higher density of the corticospinal tract in the central and caudal parts of the injured spinal cord. Luxol fast blue and toluidine blue staining showed that the volume of residual myelin was significantly increased at 1 and 2 mm rostral and caudal to the lesion epicenter after cell transplantation. Furthermore, immunofluorescence staining verified that the newly regenerated myelin sheath was derived from the central nervous system. Basso, Beattie and Bresnahan testing showed an evident behavioral recovery. These results suggest that human umbilical mesenchymal stem cell-derived oligodendrocyte precursor cells promote the regeneration of spinal axons and myelin sheaths.

Association between Alzheimer's disease pathogenesis and early demyelination and oligodendrocyte dysfunction

The APPSwe/PSEN1 dE9（APP/PS1） transgenic mouse model is an Alzheimer＇s disease mouse model exhibiting symptoms of dementia, and is commonly used to explore pathological changes in the development of Alzheimer＇s disease. Previous clinical autopsy and imaging studies suggest that Alzheimer＇s disease patients have white matter and oligodendrocyte damage, but the underlying mechanisms of these have not been revealed. Therefore, the present study used APP/PS1 mice to assess cognitive change, myelin loss, and corresponding changes in oligodendrocytes, and to explore the underlying mechanisms. Morris water maze tests were performed to evaluate cognitive change in APP/PS1 mice and normal C57 BL/6 mice aged 3 and 6 months. Luxol fast blue staining of the corpus callosum and quantitative reverse transcription-polymerase chain reaction（q RT-PCR） for myelin basic protein（MBP） mRNA were carried out to quantify myelin damage. Immunohistochemistry staining for NG2 and qRT-PCR for monocarboxylic acid transporter 1（MCT1） mRNA were conducted to assess corresponding changes in oligodendrocytes. Our results demonstrate that compared with C57 BL/6 mice, there was a downregulation of MBP mRNA in APP/PS1 mice aged 3 months. This became more obvious in APP/PS1 mice aged 6 months accompanied by other abnormalities such as prolonged escape latency in the Morris water maze test, shrinkage of the corpus callosum, upregulation of NG2-immunoreactive cells, and downregulation of MCT1 mRNA. These findings indicate that the involvement of early demyelination at 3 months and the oligodendrocyte dysfunction at 6 months in APP/PS1 mice are in association with Alzheimer＇s disease pathogenesis.

Axonal damage in myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis in a C57BL/6 mouse model may be not secondary to inflammatory demyelination

The present study established a chronic experimental autoimmune encephalomyelitis model in C57BL/6 mice induced by myelin oligodendrocyte glycoprotein peptides and complete Freund＇s adjuvant. Onset latency was 12 days, with an incidence rate of 100%. Neuropathological characteristics included perivascular inflammatory cell infiltration, demyelination, neuronal degeneration, and axonal damage within cerebral and myelic white matter. Electron microscopy revealed swollen mitochondria, complete organ disappearance, and fused or broken myelin sheath structure, which were accompanied by myelin sheath reconstruction. Moreover, axonal damage was not consistent with demyelination distribution, and severity of axonal damage did not correlate with demyelination. Results suggested that axonal damage in an experimental autoimmune encephalomyelitis model is not secondary to inflammatory demyelination.

Star power: harnessing the reactive astrocyte response to promote remyelination in multiple sclerosis

Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models.We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination.Finally,we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.

Overlapping syndrome of recurrent anti-N-methyl-D-aspartate receptor encephalitis and anti-myelin oligodendrocyte glycoprotein demyelinating diseases:A case report

BACKGROUND Anti-N-methyl-D-aspartate receptor encephalitis(NMDARe)is capable of presenting a relapsing course and coexisting with myelin oligodendrocyte glycoprotein antibody disease,whereas it has been relatively rare.We describe a man with no history of tumor who successively developed anti-NMDARe and anti-myelin oligodendrocyte glycoprotein antibody disease.CASE SUMMARY A 29-year-old man was initially admitted with headache,fever,intermittent abnormal behavior,decreased intelligence,limb twitching and loss of consciousness on July 16,2018.On admission,examination reported no abnormality.During his presentation,he experienced aggravated symptoms,and the reexamination of cranial magnetic resonance imaging(MRI)indicated punctate abnormal signals in the left parietal lobe.External examination of cerebrospinal fluid and serum results revealed serum NMDAR antibody(Ab)(-),cerebrospinal fluid NMDAR-Ab(+)1:10 and Epstein-Barr virus capsid antigen antibody Ig G(+).Due to the imaging findings,anti-NMDARe was our primary consideration.The patient was treated with methylprednisolone and gamma globulin pulse therapy,mannitol injection dehydration to reduce intracranial pressure,sodium valproate sustained-release tablets for anti-epilepsy and olanzapine and risperidone to mitigate psychiatric symptoms.The patient was admitted to the hospital for the second time for“abnormal mental behavior and increased limb movements”on December 14,2018.Re-examination of electroencephalography and cranial MRI showed no abnormality.The results of autoimmune encephalitis antibody revealed that serum NMDAR-Ab was weakly positive and cerebrospinal fluid NMDAR-Ab was positive.Considering comprehensive recurrent anti-NMDARe,the patient was treated with propylene-hormone pulse combined with immunosuppressive agents(mycophenolate mofetil),and the symptoms were relieved.The patient was admitted for“hoarseness and double vision”for the third time on August 23,2019.Re-examination of cranial MRI showed abnormal signals in the medulla oblongata and right frontal lobe,and synoptophore examination indicated concomitant esotropia.The patient’s visual acuity further decreased,and the reexamination of cranial MRI+enhancement reported multiple scattered speckled and patchy abnormal signals in the medulla oblongata,left pons arm,left cerebellum and right midbrain,thalamus.The patient was diagnosed with an accompanying demyelinating disease.Serum antimyelin oligodendrocyte glycoprotein 1:10 and NMDAR antibody 1:10 were both positive.The patient was diagnosed with myelin oligodendrocyte glycoprotein antibody-related inflammatory demyelinating disease of the central nervous system complicated with anti-NMDARe overlap syndrome.The patient was successfully treated with methylprednisolone,gamma globulin pulse therapy and rituximab treatment.The patient remained asymptomatic and follow-up MRI scan 6 mo later showed complete removal of the lesion.CONCLUSION We emphasize the rarity of this antibody combination and suggest that these patients may require longer follow-up due to the risk of recurrence of two autoimmune disorders.

Neuromyelitis optica and myelin oligodendrocyte glycoprotein

Neuromyelitis optica(NMO)refers to an antibody mediated,inflammatory disorder of the central nervous system(CNS)characterized by recurrent or monophasic attacks of optic neuritis and myelitis.Most patients with NMO possess a specific serum immunoglobin,NMO-IgG,which can serve as a biomarker for NMO.The autoantibodies target aquaporin-4(AQP4),the main water channel protein found in the CNS including the brain,spinal cord,and optic nerve.The remaining 10-25%of patients are seronegative for NMO-IgG despite meeting the diagnostic criteria for NMO.Recent studies have shown that a subset of these patients is seropositive for antibodies against myelin oligodendrocyte glycoprotein(MOG).This paper will provide an overview of the current English scientific literature published regarding the history,epidemiology,AQP4 biomarker,MOG biomarker,diagnosis,clinical features,related diseases in NMO spectrum disorder(NMOSD),and treatments of NMO.

Proteomic profiling of cerebrospinal fluid in pediatric myelin oligodendrocyte glycoprotein antibody-associated disease

Background Myelin oligodendrocyte glycoprotein(MOG)antibody-associated disease(MOGAD)is an autoimmune demy-elinating disorder of the central nervous system.Methods Extracted proteins from 34 cerebrospinal fluid(CSF)samples[patients with MOGAD(MOG group,n=12);healthy controls(HC group,n=12);patients with MOG seronegative and metagenomics next-generation sequencing-negative inflammatory neurological diseases(IND group,n=10)]were processed and subjected to label-free quantitative proteomics.Supervised partial least squares-discriminant analysis(PLS-DA)and orthogonal PLS-DA(O-PLS-DA)models were also performed based on proteomics data.Functional analysis of differentially expressed proteins(DEPs)was performed using Gene Ontology,InterPro,and Kyoto Encyclopedia Genes and Genomes.An enzyme-linked immunosorbent assay was used to determine the complement levels in serum from patients with MOGAD.Results Four hundred and twenty-nine DEPs(149 upregulated and 280 downregulated proteins)were identified in the MOG group compared to the HC group according to the P value and fold change(FC).Using the O-PLS-DA model,872 differentially abundant proteins were identified with variable importance projection(VIP)scores>1.Five proteins(gamma-glutamyl hydrolase,cathepsin F,interalpha-trypsin inhibitor heavy chain 5,latent transforming growth factor beta-binding protein 4 and leukocyte-associated immunoglobulin-like receptor 1)overlapping between the top 30 DEPs with top-ranked P value and FC and top 30 proteins in PLS-DA VIP lists were acquired.Functional analysis revealed that the dysregulated proteins in the MOG group were primarily involved in complement and coagulation cascades,cell adhesion,axon guidance,and glycosphingolipid biosynthesis compared to the HC group.Conclusion The proteomic alterations in CSF samples from children with MOGAD identified in the current study might provide opportunities for developing novel biomarker candidates.

Trophic factors are essential for the survival of grafted oligodendrocyte progenitors and for neuroprotection after perinatal excitotoxicity

The consequences of neonatal white matter injury are devastating and represent a major societal problem as currently there is no cure.Prematurity,low weight birth and maternal pre-natal infection are the most frequent causes of acquired myelin deficiency in the human neonate leading to cerebral palsy and cognitive impairment.In the developing brain,oligodendrocyte(OL)maturation occurs perinatally,and immature OLs are particularly vulnerable.Cell replacement therapy is often considered a viable option to replace progenitors that die due to glutamate excitotoxicity.We previously reported directed specification and mobilization of endogenous committed and uncommitted neural progenitors by the combination of transferrin and insulin growth factor 1(TSC1).Here,considering cell replacement and integration as therapeutic goals,we examined if OL progenitors(OLPs)grafted into the brain parenchyma of mice that were subjected to an excitotoxic insult could rescue white matter injury.For that purpose,we used a well-established model of glutamate excitotoxic injury.Four-day-old mice received a single intraparenchymal injection of the glutamate receptor agonist N-methyl-D-aspartate alone or in conjunction with TSC1 in the presence or absence of OLPs grafted into the brain parenchyma.Energetics and expression of stress proteins and OL developmental specific markers were examined.A comparison of the proteomic profile per treatment was also ascertained.We found that OLPs did not survive in the excitotoxic environment when grafted alone.In contrast,when combined with TSC1,survival and integration of grafted OLPs was observed.Further,energy metabolism in OLPs was significantly increased by N-methyl-D-aspartate and modulated by TSC1.The proteomic profile after the various treatments showed elevated ubiquitination and stress/heat shock protein 90 in response to N-methyl-D-aspartate.These changes were reversed in the presence of TSC1 and ubiquitination was decreased.The results obtained in this pre-clinical study indicate that the use of a combinatorial intervention including both trophic support and healthy OLPs constitutes a promising approach for long-term survival and successful graft integration.We established optimal conditioning of the host brain environment to promote long-term survival and integration of grafted OLPs into an inflamed neonate host brain.Experimental procedures were performed under the United States Public Health Service Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care Committee at(UCLA)(ARC#1992-034-61)on July 1,2010.

Transferrin receptor and ferritin-H are developmentally regulated in oligodendrocyte lineage cells

Iron is an essential trophic element that is required for cell viability and differentiation, especially in oligodendrocytes, which consume relatively high rates of energy to produce myelin. Multiple iron metabolism proteins are expressed in the brain including transferrin receptor and ferritin-H. However, it is still unknown whether they are developmentally regulated in oligodendrocyte lineage cells for myelination. Here, using an in vitro cultured differentiation model of oligodendrocytes, we found that both transferrin receptor and ferritin-H are significantly upregulated during oligodendrocyte maturation, implying the essential role of iron in the development of oligodendrocytes. Additional different doses of Fe3＋ in the cultured medium did not affect oligodendrocyte precursor cell maturation or ferritin-H expression but decreased the expression of the transferrin receptor. These results indicate that upregulation of both transferrin receptor and ferritin-H contributes to maturation and myelination of oligodendrocyte precursor cells.

Progesterone effects on the oligodendrocyte linage: all roads lead to the progesterone receptor

A new role has emerged for progesterone after discovering its potent actions away from reproduction in both the central and the peripheral nervous system. The aim of the present report is to discuss progesterone’s mechanisms of action involved in myelination, remyelination and neuroinflammation. The pivotal role of the classic progesterone receptor is described and evidence is compiled about progesterone’s direct effects on oligodendrocyte linage and its indirect effects on oligodendrocyte precursor cell differentiation by decreasing the neuroinflammatory environment.

Oligodendrocyte pathology in fetal alcohol spectrum disorders

The pathology of fetal alcohol syndrome and the less severe fetal alcohol spectrum disorders includes brain dysmyelination.Recent studies have shed light on the molecular mechanisms underlying these white matter abnormalities.Rodent models of fetal alcohol syndrome and human studies have shown suppressed oligodendrocyte differentiation and apoptosis of oligodendrocyte precursor cells.Ethanol exposure led to reduced expression of myelin basic protein and delayed myelin basic protein expression in rat and mouse models of fetal alcohol syndrome and in human histopathological specimens.Several studies have reported increased expression of many chemokines in dysmyelinating disorders in central nervous system,including multiple sclerosis and fetal alcohol syndrome.Acute ethanol exposure reduced levels of the neuroprotective insulin-like growth factor-1 in fetal and maternal sheep and in human fetal brain tissues,while ethanol increased the expression of tumor necrosis factor α in mouse and human neurons.White matter lesions have been induced in the developing sheep brain by alcohol exposure in early gestation.Rat fetal alcohol syndrome models have shown reduced axon diameters,with thinner myelin sheaths,as well as reduced numbers of oligodendrocytes,which were also morphologically aberrant oligodendrocytes.Expressions of markers for mature myelination,including myelin basic protein,also were reduced.The accumulating knowledge concerning the mechanisms of ethanol-induced dysmyelination could lead to the development of strategies to prevent dysmyelination in children exposed to ethanol during fetal development.Future studies using fetal oligodendrocyte-and oligodendrocyte precursor cell-derived exosomes isolated from the mother's blood may identify biomarkers for fetal alcohol syndrome and even implicate epigenetic changes in early development that affect oligodendrocyte precursor cell and oligodendrocyte function in adulthood.By combining various imaging modalities with molecular studies,it may be possible to determine which fetuses are at risk and to intervene therapeutically early in the pregnancy.

An Alzheimer's Disease-Relevant Presenilin-1 Mutation Augments Amyloid-Beta-Induced Oligodendrocyte Dysfunction

研究表明,家族性阿尔茨海默病(FAD)患者处于无症状或临床前阶段时,脑白质即出现病理改变。此种改变在髓鞘破坏及阿尔茨海默病(AD)病理生理中的作用有待进一步研究阐明。笔者前期研究证实,三重转基因AD小鼠(人淀粉前体蛋白基因的Swedish突变,早老素-1 M146V(PS1M146V)敲入突变及tauP301L突变)表现出类似FAD患者的髓鞘破坏,Aβ1-42促进了白质病变。本研究离体实验证实,PS1M146V变异导致小鼠少突胶质前体细胞在分化过程中易出现类似Aβ1-42诱导的变化。PS1M146V的表达损伤少突胶质前体细胞的功能并影响髓鞘碱性蛋白的分布,暴露于Aβ1-42加重此影响。由PS1M146V及Aβ1-42导致的髓鞘破坏及髓鞘碱性蛋白在亚细胞结构中的误定位可被TWS119(糖原合成激酶(GSK)-3β抑制剂)抑制,提示GSK-3β激酶活动在此病理过程中有重要作用。综上所述,本研究有助于增加对AD早期无症状阶段,由PS1M146V及Aβ1-42导致少突胶质细胞功能异常及髓鞘损伤的机制的理解,并提供了针对少突胶质细胞预防AD相关白质病变的新的治疗靶点。

Embracing oligodendrocyte diversity in the context of perinatal injury

Emerging evidence is fueling a new appreciation of oligodendrocyte diversity that is overturning the traditional view that oligodendrocytes are a homogenous cell population.Oligodendrocytes of distinct origins,maturational stages,and regional locations may differ in their functional capacity or susceptibility to injury.One of the most unique qualities of the oligodendrocyte is its ability to produce myelin.Myelin abnormalities have been ascribed to a remarkable array of perinatal brain injuries,with concomitant oligodendrocyte dysregulation.Within this review,we discuss new insights into the diversity of the oligodendrocyte lineage and highlight their relevance in paradigms of perinatal brain injury.Future therapeutic development will be informed by comprehensive knowledge of oligodendrocyte pathophysiology that considers the particular facets of heterogeneity that this lineage exhibits.

Oligodendrocytes in Mouse Corpus Callosum are Coupled Via Gap Junction Channels Formed by Connexin47 and Connexin32

已有的超微结构研究显示,白质中的少突胶质细胞和星形胶质细胞之间存在缝隙连接,但少突胶质细胞之间不存在缝隙连接,虽然体外培养的少突胶质细胞可形成功能性缝隙连接。本文研究新生小鼠胼胝体急性脑片中的少突胶质细胞的功能性连接。以全细胞膜片钳技术用生物胞素(一种可渗透的缝隙连接示踪剂)标记少突胶质细胞。平均61个细胞为链霉亲和素-Cy3标记的生物胞素阳性。约77%的连结细胞表达少突胶质细胞标志蛋白CNPase阳性染色,9%表达星形胶质细胞标志蛋白GFAP阳性,14%为CNPase和GFAP阴性。后者的大部分表达Olig2和一些NG2(少突胶质细胞前体细胞的标志物)。少突胶质细胞表达Cx47、Cx32和Cx29,星形胶质细胞表达Cx43和Cx30。在Cx47敲除小鼠中,连结细胞的数量减少80%。单独删除Cx32或Cx29并不能显著减少连结细胞的数量,但Cx32/Cx47双缺陷小鼠中没有观察到相互连结的细胞。Cx47敲除完全消除了少突胶质细胞与星形胶质细胞间的耦联。在Cx43敲除动物中,少突胶质细胞-星形胶质细胞间连接仍然存在,但与少突胶质细胞前体细胞间的耦联没有被观察到。在Cx43/Cx30双敲除小鼠中,少突胶质细胞-星形胶质细胞连接几乎不存在。解开连结的少突胶质细胞显示为较高的膜输入电阻。本文认为,白质中的少突胶质细胞依靠Cx47和Cx32的表达形成功能性的合胞体,而星形胶质蛋白缝隙连接蛋白的表达能提升此网络的大小。

Clemastine in remyelination and protection of neurons and skeletal muscle after spinal cord injury

Spinal cord injuries affect nearly five to ten individuals per million every year. Spinal cord injury causes damage to the nerves, muscles, and the tissue surrounding the spinal cord. Depending on the severity, spinal injuries are linked to degeneration of axons and myelin, resulting in neuronal impairment and skeletal muscle weakness and atrophy. The protection of neurons and promotion of myelin regeneration during spinal cord injury is important for recovery of function following spinal cord injury. Current treatments have little to no effect on spinal cord injury and neurogenic muscle loss. Clemastine, an Food and Drug Administration-approved antihistamine drug, reduces inflammation, protects cells, promotes remyelination, and preserves myelin integrity. Recent clinical evidence suggests that clemastine can decrease the loss of axons after spinal cord injury, stimulating the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes that are capable of myelination. While clemastine can aid not only in the remyelination and preservation of myelin sheath integrity, it also protects neurons. However, its role in neurogenic muscle loss remains unclear. This review discusses the pathophysiology of spinal cord injury, and the role of clemastine in the protection of neurons, myelin, and axons as well as attenuation of skeletal muscle loss following spinal cord injury.

Piezo1 suppression reduces demyelination after intracerebral hemorrhage

Piezo1 is a mechanically-gated calcium channel.Recent studies have shown that Piezo1,a mechanically-gated calcium channel,can attenuate both psychosineand lipopolysaccharide-induced demyelination.Because oligodendrocyte damage and demyelination occur in intracerebral hemorrhage,in this study,we investigated the role of Piezo1 in intracerebral hemorrhage.We established a mouse model of cerebral hemorrhage by injecting autologous blood into the right basal ganglia and found that Piezo1 was largely expressed soon(within 48 hours)after intracerebral hemorrhage,primarily in oligodendrocytes.Intraperitoneal injection of Dooku1 to inhibit Piezo1 resulted in marked alleviation of brain edema,myelin sheath loss,and degeneration in injured tissue,a substantial reduction in oligodendrocyte apoptosis,and a significant improvement in neurological function.In addition,we found that Dooku1-mediated Piezo1 suppression reduced intracellular endoplasmic reticulum stress and cell apoptosis through the PERK-ATF4-CHOP and inositol-requiring enzyme 1 signaling pathway.These findings suggest that Piezo1 is a potential therapeutic target for intracerebral hemorrhage,as its suppression reduces intracellular endoplasmic reticulum stress and cell apoptosis and protects the myelin sheath,thereby improving neuronal function after intracerebral hemorrhage.

Expression of hypoxia-inducible factor 1 alpha and oligodendrocyte lineage gene-1 in cultured brain slices after oxygen-glucose deprivation

Oligodendrocyte lineage gene-1 expressed in oligodendrocytes may trigger the repair of neuronal myelin impairment, and play a crucial role in myelin repair. Hypoxia-inducible factor la, a transcription factor, is of great significance in premature infants with hypoxic-ischemic brain damage There is little evidence of direct regulatory effects of hypoxia-inducible factor le on oligodendrocyte lineage gene-l. In this study, brain slices of Sprague-Dawley rats were cultured and subjected to oxygen-glucose deprivation. Then, slices were transfected with hypoxia-inducible factor la or oligodendrocyte lineage gene-1. The expression levels of hypoxia-inducible factor la and oligodendrocyte lineage gene-1 were significantly up-regulated in rat brains prior to transfection, as detected by immunohistochemical staining. Eight hours after transfection of slices with hypoxia-inducible factor la, oligodendrocyte lineage gene-1 expression was upregulated, and reached a peak 24 hours after transfection. Oligodendrocyte lineage gene-1 transfection induced no significant differences in hypoxia-inducible factor la levels in rat brain tissues with oxygen-glucose deprivation. These experimental findings indicate that hypoxia-inducible factor la can regulate oligodendrocyte lineage gene-1 expression in hypoxic brain tissue, thus repairing the neural impairment.

CB_1 Cannabinoid Receptor-Dependent and-Independent Inhibition of Depolarization-Induced Calcium Influx in Oligodendrocytes

Ca2+稳态平衡的调节在少突胶质细胞功能和存活中起重要作用。大麻素CB1和CB2受体在许多细胞中调节Ca2+水平和/或K+电流。本文利用培养的少突胶质细胞中,通过增高细胞外K+浓度(50 mM诱导膜去极化,研究大麻素复合物在此过程引发钙内流中的作用。CB2受体激动剂ACEA导致去极化诱导的少突胶质细胞胞浆的Ca2+瞬变表达浓度依赖性抑制,最大效应为(94±3)%,半效应浓度(EC50)为(1.3±0.03)μM。这种作用可被CB2/CB2激动剂CP55、940、内源性大麻素类AEA和2-AG所模拟,但是CB2受体选择性激动剂J WH133没有作用。CB2受体拮抗剂AM251(1μM)也可减少细胞外高K+诱导的Ca2+反应,但不能防止ACEA(3μM)诱发的抑制效应。然而,ACEA和AEA减少去极化诱导的Ca2+瞬变的能力在CB2受体敲除小鼠和经百日咳毒素预处理的少突胶质细胞中明显降低。内流性K+通道阻断剂BaCl2(300μM)和CsCl2(1 mM)降低电压诱导的Ca2+内流并部分阻断ACEA的抑制效应。本文表明,大麻素抑制少突胶质细胞中去极化诱导的Ca2+瞬变是通过包括PTX-敏感的Gi/o蛋白和阻断K+内流通道的CB2受体依赖性和非依赖性机制。

Perilipin-2 mediates ferroptosis in oligodendrocyte progenitor cells and myelin injury after ischemic stroke

Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage.Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation,and plays an important role in the pathological process of ischemic stroke.However,there are few studies on oligodendrocyte progenitor cell ferroptosis.We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia.Bioinformatics analysis suggested that perilipin-2(PLIN2)was involved in oligodendrocyte progenitor cell ferroptosis.PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation.For further investigation,we established a mouse model of cerebral ischemia/reperfusion.We found significant myelin damage after cerebral ischemia,as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area.The ferroptosis inhibitor,ferrostatin-1,rescued oligodendrocyte progenitor cell death and subsequent myelin injury.We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells.Plin2 knockdown rescued demyelination and improved neurological deficits.Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia.