Oligodendrocyte Survival Research Articles

Endogenous histidine peptides are physiological antioxidants that prevent oligodendrocyte cell death and myelin loss in vivo.

Histidine dipeptides (HDs) are synthesized in brain oligodendrocytes by carnosine synthase (carns1), but their role is unknown. Using metabolomics and in vivo experiments with both constitutive and oligodendrocyte-selective carns1-KO mouse models, we found that HDs are critical for oligodendrocyte survival and protect against oxidative stress. Carns1-KO mouse models had lower numbers of mature oligodendrocytes, increased lipid peroxidation, and behavioral changes. Cuprizone administration, which increases reactive oxygen species in vivo, resulted in higher oligodendrocyte death, demyelination, axonal alterations, and oxidative damage in the corpus callosum of carns1-KO mice. Gliosis and oxidative damage by cuprizone were prevented by pretreatment with the antioxidant N-acetylcysteine. NADPH levels were increased threefold in the brains of carns1-KO mice as an antioxidant response to oxidative stress through acceleration of the pentose phosphate pathway (PPP). This was due to overexpression of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the PPP. Likewise, expression of NAD kinase, the biosynthetic enzyme for NADP+, and NAMPT, which replenishes the NAD+ pool, was higher in carns1-KO mice brains than in controls. Our observations suggest that HDs cell-autonomously protect oligodendrocytes from oxidative stress, with implications for demyelinating diseases.

Oligodendrocytes go with the flow: Meningeal lymphatics promote myelin integrity

The meningeal lymphatics system plays diverse roles in facilitating neuroimmune function at brain borders, yet its specific contribution toward glial function and homeostasis is not known. In this issue of Immunity, Das Neves etal. (2024) describe a novel role for the meningeal lymphatics in maintaining oligodendrocyte survival and myelination.

Neurotropic Murine β-Coronavirus Infection Causes Differential Expression of Connexin 47 in Oligodendrocyte Subpopulations Associated with Demyelination.

Gap junctions (GJs) play a crucial role in the survival of oligodendrocytes and myelination of the central nervous system (CNS). In this study, we investigated the spatiotemporal changes in the expression of oligodendroglial GJ protein connexin 47 (Cx47), its primary astroglial coupling partner, Cx43, and their association with demyelination following intracerebral infection with mouse hepatitis virus (MHV). Neurotropic strains of MHV, a β-coronavirus, induce an acute encephalomyelitis followed by a chronic demyelinating disease that shares similarities with the human disease multiple sclerosis (MS). Our results reveal that Cx47 GJs are persistently lost in mature oligodendrocytes, not only in demyelinating lesions but also in surrounding normal appearing white and gray matter areas, following an initial loss of astroglial Cx43 GJs during acute infection. At later stages after viral clearance, astroglial Cx43 GJs re-emerge but mature oligodendrocytes fail to fully re-establish GJs with astrocytes due to lack of Cx47 GJ expression. In contrast, at this later demyelinating stage, the increased oligodendrocyte precursor cells appear to exhibit Cx47 GJs. Our findings further highlight varying degrees of demyelination in distinct spinal cord regions, with the thoracic cord showing the most pronounced demyelination. The regional difference in demyelination correlates well with dynamic changes in the proportion of different oligodendrocyte lineage cells exhibiting differential Cx47 GJ expression, suggesting an important mechanism of progressive demyelination even after viral clearance.

Ferritin loss in astrocytes reduces spinal cord oxidative stress and demyelination in the experimental autoimmune encephalomyelitis (EAE) model.

Demyelinating diseases such as multiple sclerosis (MS) cause myelin degradation and oligodendrocyte death, resulting in the release of toxic iron and iron-induced oxidative stress. Astrocytes have a large capacity for iron transport and storage, however the role of astrocytic iron homeostasis in demyelinating disorders is not completely understood. Here we investigate whether astrocytic iron metabolism modulates neuroinflammation, oligodendrocyte survival, and oxidative stress following demyelination. To this aim, we conditionally knock out ferritin in astrocytes and induce experimental autoimmune encephalomyelitis (EAE), an autoimmune-mediated model of demyelination. Ferritin ablation in astrocytes reduced the severity of disease in both the acute and chronic phases. The day of onset, peak disease severity, and cumulative clinical score were all significantly reduced in ferritin KO animals. This corresponded to better performance on the rotarod and increased mobility in ferritin KO mice. Furthermore, the spinal cord of ferritin KO mice display decreased numbers of reactive astrocytes, activated microglia, and infiltrating lymphocytes. Correspondingly, the size of demyelinated lesions, iron accumulation, and oxidative stress were attenuated in the CNS of ferritin KO subjects, particularly in white matter regions of the spinal cord. Thus, deleting ferritin in astrocytes reduced neuroinflammation, oxidative stress, and myelin deterioration in EAE animals. Collectively, these findings suggest that iron storage in astrocytes is a potential therapeutic target to lessen CNS inflammation and myelin loss in autoimmune demyelinating diseases.

Low intensity repetitive transcranial magnetic stimulation enhances remyelination by newborn and surviving oligodendrocytes in the cuprizone model of toxic demyelination

In people with multiple sclerosis (MS), newborn and surviving oligodendrocytes (OLs) can contribute to remyelination, however, current therapies are unable to enhance or sustain endogenous repair. Low intensity repetitive transcranial magnetic stimulation (LI-rTMS), delivered as an intermittent theta burst stimulation (iTBS), increases the survival and maturation of newborn OLs in the healthy adult mouse cortex, but it is unclear whether LI-rTMS can promote remyelination. To examine this possibility, we fluorescently labelled oligodendrocyte progenitor cells (OPCs; Pdgfrα-CreER transgenic mice) or mature OLs (Plp-CreER transgenic mice) in the adult mouse brain and traced the fate of each cell population over time. Daily sessions of iTBS (600 pulses; 120 mT), delivered during cuprizone (CPZ) feeding, did not alter new or pre-existing OL survival but increased the number of myelin internodes elaborated by new OLs in the primary motor cortex (M1). This resulted in each new M1 OL producing ~ 471 µm more myelin. When LI-rTMS was delivered after CPZ withdrawal (during remyelination), it significantly increased the length of the internodes elaborated by new M1 and callosal OLs, increased the number of surviving OLs that supported internodes in the corpus callosum (CC), and increased the proportion of axons that were myelinated. The ability of LI-rTMS to modify cortical neuronal activity and the behaviour of new and surviving OLs, suggests that it may be a suitable adjunct intervention to enhance remyelination in people with MS.

Intermittent theta-burst stimulation alleviates hypoxia-ischemia-caused myelin damage and neurologic disability

Neonatal hypoxia-ischemia (HI) results in behavioral deficits, characterized by neuronal injury and retarded myelin formation. To date, limited treatment methods are available to prevent or alleviate neurologic sequelae of HI. Intermittent theta-burst stimulation (iTBS), a non-invasive therapeutic procedure, is considered a promising therapeutic tool for treating some neurocognitive disorders and neuropsychiatric diseases. Hence, this study aims to investigate whether iTBS can prevent the negative behavioral manifestations of HI and explore the mechanisms for associations. We exposed postnatal day 10 Sprague-Dawley male and female rats to 2 h of hypoxia (6% O2) following right common carotid artery ligation, resulting in oligodendrocyte (OL) dysfunction, including reduced proliferation and differentiation of oligodendrocyte precursor cells (OPCs), decreased OL survival, and compromised myelin in the corpus callosum (CC) and hippocampal dentate gyrus (DG). These alterations were concomitant with cognitive dysfunction and depression-like behaviors. Crucially, early iTBS treatment (15 G, 190 s, seven days, initiated one day post-HI) significantly alleviated HI-caused myelin damage and mitigated the neurologic sequelae both in male and female rats. However, the late iTBS treatment (initiated 18 days after HI insult) could not significantly impact these behavioral deficits. In summary, our findings support that early iTBS treatment may be a promising strategy to improve HI-induced neurologic disability. The underlying mechanisms of iTBS treatment are associated with promoting the differentiation of OPCs and alleviating myelin damage.

Gas6/TAM system as potential biomarker for multiple sclerosis prognosis.

The protein growth arrest-specific 6 (Gas6) and its tyrosine kinase receptors Tyro-3, Axl, and Mer (TAM) are ubiquitous proteins involved in regulating inflammation and apoptotic body clearance. Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system leading to progressive and irreversible disability if not diagnosed and treated promptly. Gas6 and TAM receptors have been associated with neuronal remyelination and stimulation of oligodendrocyte survival. However, few data are available regarding clinical correlation in MS patients. We aimed to evaluate soluble levels of these molecules in the cerebrospinal fluid (CSF) and serum at MS diagnosis and correlate them with short-term disease severity. In a prospective cohort study, we enrolled 64 patients with a diagnosis of clinical isolated syndrome (CIS), radiological isolated syndrome (RIS) and relapsing-remitting (RR) MS according to the McDonald 2017 Criteria. Before any treatment initiation, we sampled the serum and CSF, and collected clinical data: disease course, presence of gadolinium-enhancing lesions, and expanded disability status score (EDSS). At the last clinical follow-up, we assessed EDSS and calculated MS severity score (MSSS) and age-related MS severity (ARMSS). Gas6 and TAM receptors were determined using an ELISA kit (R&D Systems) and compared to neurofilament (NFLs) levels evaluated with SimplePlex™ fluorescence-based immunoassay. At diagnosis, serum sAxl was higher in patients receiving none or low-efficacy disease-modifying treatments (DMTs) versus patients with high-efficacy DMTs (p = 0.04). Higher CSF Gas6 and serum sAXL were associated with an EDSS<3 at diagnosis (p = 0.04; p = 0.037). Serum Gas6 correlates to a lower MSSS (r2 = -0.32, p = 0.01). Serum and CSF NFLs were confirmed as disability biomarkers in our cohort according to EDSS (p = 0.005; p = 0.002) and MSSS (r2= 0.27, p = 0.03; r2 = 0.39, p = 0.001). Results were corroborated using multivariate analysis. Our data suggest a protective role of Gas6 and its receptors in patients with MS and suitable severity disease biomarkers.

Gamma entrainment using audiovisual stimuli alleviates chemobrain pathology and cognitive impairment induced by chemotherapy in mice.

Patients with cancer undergoing chemotherapy frequently experience a neurological condition known as chemotherapy-related cognitive impairment, or "chemobrain," which can persist for the remainder of their lives. Despite the growing prevalence of chemobrain, both its underlying mechanisms and treatment strategies remain poorly understood. Recent findings suggest that chemobrain shares several characteristics with neurodegenerative diseases, including chronic neuroinflammation, DNA damage, and synaptic loss. We investigated whether a noninvasive sensory stimulation treatment we term gamma entrainment using sensory stimuli (GENUS), which has been shown to alleviate aberrant immune and synaptic pathologies in mouse models of neurodegeneration, could also mitigate chemobrain phenotypes in mice administered a chemotherapeutic drug. When administered concurrently with the chemotherapeutic agent cisplatin, GENUS alleviated cisplatin-induced brain pathology, promoted oligodendrocyte survival, and improved cognitive function in a mouse model of chemobrain. These effects persisted for up to 105 days after GENUS treatment, suggesting the potential for long-lasting benefits. However, when administered to mice 90 days after chemotherapy, GENUS treatment only provided limited benefits, indicating that it was most effective when used to prevent the progression of chemobrain pathology. Furthermore, we demonstrated that the effects of GENUS in mice were not limited to cisplatin-induced chemobrain but also extended to methotrexate-induced chemobrain. Collectively, these findings suggest that GENUS may represent a versatile approach for treating chemobrain induced by different chemotherapy agents.

Oligodendrocyte Maturation Alters the Cell Death Mechanisms That Cause Demyelination.

Myelinating oligodendrocytes die in human disease and early in aging. Despite this, the mechanisms that underly oligodendrocyte death are not resolved and it is also not clear whether these mechanisms change as oligodendrocyte lineage cells are undergoing differentiation and maturation. Here, we used a combination of intravital imaging, single-cell ablation, and cuprizone-mediated demyelination, in both female and male mice, to discover that oligodendrocyte maturation dictates the dynamics and mechanisms of cell death. After single-cell phototoxic damage, oligodendrocyte precursor cells underwent programmed cell death within hours, differentiating oligodendrocytes died over several days, while mature oligodendrocytes took weeks to die. Importantly cells at each maturation stage all eventually died but did so with drastically different temporal dynamics and morphological features. Consistent with this, cuprizone treatment initiated a caspase-3-dependent form of rapid cell death in differentiating oligodendrocytes, while mature oligodendrocytes never activated this executioner caspase. Instead, mature oligodendrocytes exhibited delayed cell death which was marked by DNA damage and disruption in poly-ADP-ribose subcellular localization. Thus, oligodendrocyte maturation plays a key role in determining the mechanism of death a cell undergoes in response to the same insult. This means that oligodendrocyte maturation is important to consider when designing strategies for preventing cell death and preserving myelin while also enhancing the survival of new oligodendrocytes in demyelinating conditions.

Abstract WP58: Intermittent Theta-Burst Stimulation Attenuates Oligodendrocytes Dysfunction and Alleviates Depression-Like Behaviors in Hypoxia-Ischemia Rats

Rationale: Perinatal hypoxic-ischemic (HI) brain injury is a significant cause of mortality and morbidity among newborns. Children who survive newborn hypoxic-ischemic encephalopathy (HIE) are at an increased risk of developing mood disturbances, characterized by neuronal injury and retarded myelin formation. To date, limited treatment methods are available to prevent or alleviate neurologic sequelae of HI. Intermittent theta-burst stimulation (iTBS) is considered a promising therapeutic tool for treating neuropsychiatric diseases. Hence, this study aims to investigate whether iTBS can prevent the negative behavioral manifestations of HI and explore the mechanisms for associations. Methods: Postnatal day 10 Sprague-Dawley male and female rats were subjected to hypoxic (6% O 2 ) conditions for 2 h after ligating the right common carotid artery. Transcranial application of iTBS (15 Gauss) was administered daily for seven consecutive days, starting either one day after HI insult (early iTBS) or 18 days after HI insult (late iTBS). Depression-like behaviors were examined 5 weeks after HI. The levels of oligodendrocyte progenitor cells (OPCs) proliferation, differentiation, and apoptosis, as well as the myelinating of oligodendrocytes (OLs) were measured and analyzed using immunofluorescence staining and automated western blot. Results: The male and female rats exposed to HI exhibited apparent OLs dysfunction, including a decrease in OPCs proliferation, a reduction in OPCs differentiation, diminished survival of OLs, and hindered myelination in the corpus callosum (CC) area. These alternations were concomitant with depression-like behaviors. Crucially, early iTBS treatment significantly alleviated HI-caused myelination damage and mitigated the neurologic sequelae both in male and female rats. However, the late iTBS treatment could not significantly impact these behavioral deficits. Conclusion: Our findings support that early iTBS treatment may be a promising strategy to improve HI-induced neurologic disability. The underlying mechanisms are suggested to be associated with the promoted the differentiation of OPCs and the alleviated myelination damage following iTBS administration.

Improved Efficacy of Delayed Treatment with Human Bone Marrow-Derived Stromal Cells Evaluated in Rats with Spinal Cord Injury.

The treatment of spinal cord injury (SCI) with uncultivated human bone marrow-derived stromal cells (bmSCs) prepared by negative selection has been proposed to be therapeutically superior to treatment with stem cells that were expanded in vitro. To explore their use in clinical trials, we studied the functional effects of delayed application at 7 days after SCI by testing different doses of bmSCs. Spinal cord contusion injury was induced in adult male Wistar rats at the thoracic level T9. Human bmSCs were prepared by negative selection without expansion in vitro (NeuroCellsTM). Treatment consisted of one 150 µL injection into the cisterna magna containing 0.5 or 2.5 million fresh bmSCs or 2.5 million bmSCs. The recovery of motor functions was evaluated during a surveillance period of six weeks (6 W), during which spinal cords were assessed histologically. Treatment resulted in a significant, dose-dependent therapeutic effect on the recovery of motor performance. The histological analysis revealed a lower degree of axonal degeneration and better survival of neurons and oligodendrocytes in bmSCs treated rats. Our results support delayed intrathecal application of bmSCs prepared by negative selection without expansion in vitro as a treatment of SCI.

Celastrol inhibits oligodendrocyte and neuron ferroptosis to promote spinal cord injury recovery

BackgroundSpinal cord injury (SCI) is a traumatic injury to the central nervous system and can cause lipid peroxidation in the spinal cord. Ferroptosis, an iron-dependent programmed cell death, plays a key role in the pathophysiology progression of SCI. Celastrol, a widely used antioxidant drug, has potential therapeutic value for nervous system. PurposeTo investigate whether celastrol can be a reliable candidate for ferroptosis inhibitor and the molecular mechanism of celastrol in repairing SCI by inhibiting ferroptosis. MethodsFirst, a rat SCI model was constructed, and the recovery of motor function was observed after treatment with celastrol. The regulatory effect of celastrol on ferroptosis pathway Nrf2-xCT-GPX4 was detected by Western blot and immunofluorescence. Finally, the ferroptosis model of neurons and oligodendrocytes was constructed in vitro to further verify the mechanism of inhibiting ferroptosis by celastrol. ResultsOur results demonstrated that celastrol promoted the recovery of spinal cord tissue and motor function in SCI rats. Further in vitro and in vivo studies showed that celastrol significantly inhibited ferroptosis in neurons and oligodendrocytes and reduced the accumulation of ROS. Finally, we found that celastrol could inhibit ferroptosis by up-regulating the Nrf2-xCT-GPX4 axis to repair SCI. ConclusionCelastrol effectively inhibits ferroptosis after SCI by upregulating the Nrf2-xCT-GPX4 axis, reducing the production of lipid ROS, protecting the survival of neurons and oligodendrocytes, and improving the functional recovery.

Mechanisms Governing Oligodendrocyte Viability in Multiple Sclerosis and Its Animal Models.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disease of the central nervous system (CNS), which is triggered by an autoimmune assault targeting oligodendrocytes and myelin. Recent research indicates that the demise of oligodendrocytes due to an autoimmune attack contributes significantly to the pathogenesis of MS and its animal model experimental autoimmune encephalomyelitis (EAE). A key challenge in MS research lies in comprehending the mechanisms governing oligodendrocyte viability and devising therapeutic approaches to enhance oligodendrocyte survival. Here, we provide an overview of recent findings that highlight the contributions of oligodendrocyte death to the development of MS and EAE and summarize the current literature on the mechanisms governing oligodendrocyte viability in these diseases.

Loss of oligodendrocyte‐derived IL‐33 results in increased amyloid plaque deposition in APP/PS1 mice

AbstractBackgroundGlial cells in the central nervous system (CNS) express IL‐33, a member of the IL‐1 family. IL‐33 is known to regulate microglial phagocytic activity toward amyloid β. In the aged brain, unlike the young counterpart, IL‐33 is predominantly expressed by oligodendrocytes (OLs), but the role of OL‐derived IL‐33 in Alzheimer’s disease (AD) is unknown.MethodOL‐specific IL‐33 conditional knockout (cKO) mice were further crossed with APPswe/Psen1 dE9 (APP/PS1) and Mobp‐EGFP transgenic mice. Cortical lysates from one‐year‐old male APP/PS1 (n = 15) and APP/PS1 + IL‐33 cKO (n = 16) mice were used for the quantitative analysis (MSD and ELISA) of amyloid β 1‐42 (Aβ1‐42) and Aβ1‐40. Immunofluorescence and morphometric analysis were also performed to measure Aβ‐covered or LAMP1‐covered areas in different regions of the mouse brain. EGFP+ OLs were also quantified.ResultsBoth Aβ1‐42 and Aβ1‐40 levels were significantly increased in the cortex (p&lt;0.0001), and so were Aβ plaque‐covered areas in the cortex, corpus callosum, and hippocampus of APP/PS1 + IL‐33 cKO mice compared with control APP/PS1 (p&lt;0.01). OL‐derived IL‐33 loss also resulted in increased accumulation of LAMP1+ dystrophic neurites (p&lt;0.05). However, cortical EGFP+ OL density was unaltered by IL‐33 cKO.ConclusionOL‐derived IL‐33 may play a regulatory role in Aβ clearance during amyloidogenesis, probably via promoting microglial activity, but not in OL survival in the AD brain. These findings support a novel mechanism of instructive interaction between OLs and microglia in disease‐associated neuroinflammation.

MSCs overexpressing GDNF restores brain structure and neurological function in rats with intracerebral hemorrhage

Mesenchymal stem cells (MSCs) have been applied in transplantation to treat intracerebral hemorrhage (ICH) but with limited efficacy. Accumulated evidence has shown that glial cell-derived neurotrophic factor (GDNF) plays a crucial part in neuronal protection and functional recovery of the brain after ICH; however, GDNF has difficulty crossing the blood–brain barrier, which limits its application. In this study, we investigated the influences of MSCs overexpressing GDNF (MSCs/GDNF) on the brain structure as well as gait of rats after ICH and explored the possible mechanisms. We found that cell transplantation could reverse the neurological dysfunction and brain damage caused by ICH to a certain extent, and MSCs/GDNF transplantation was superior to MSCs transplantation. Moreover, Transplantation of MSCs overexpressing GDNF effectively reduced the volume of bleeding foci and increased the level of glucose uptake in rats with ICH, which could be related to improving mitochondrial quality. Furthermore, GDNF produced by transplanted MSCs/GDNF further inhibited neuroinflammation, improved mitochondrial quality and function, promoted angiogenesis and the survival of neurons and oligodendrocytes, and enhanced synaptic plasticity in ICH rats when compared with simple MSC transplantation. Overall, our data indicate that GDNF overexpression heightens the curative effect of MSC implantation in treating rats following ICH.

Fecal microbial transplantation limits neural injury severity and functional deficits in a pediatric piglet traumatic brain injury model.

Pediatric traumatic brain injury (TBI) is a leading cause of death and disability in children. Due to bidirectional communication between the brain and gut microbial population, introduction of key gut bacteria may mitigate critical TBI-induced secondary injury cascades, thus lessening neural damage and improving functional outcomes. The objective of this study was to determine the efficacy of a daily fecal microbial transplant (FMT) to alleviate neural injury severity, prevent gut dysbiosis, and improve functional recovery post TBI in a translational pediatric piglet model. Male piglets at 4-weeks of age were randomly assigned to Sham + saline, TBI + saline, or TBI + FMT treatment groups. A moderate/severe TBI was induced by controlled cortical impact and Sham pigs underwent craniectomy surgery only. FMT or saline were administered by oral gavage daily for 7 days. MRI was performed 1 day (1D) and 7 days (7D) post TBI. Fecal and cecal samples were collected for 16S rRNA gene sequencing. Ipsilateral brain and ileum tissue samples were collected for histological assessment. Gait and behavior testing were conducted at multiple timepoints. MRI showed that FMT treated animals demonstrated decreased lesion volume and hemorrhage volume at 7D post TBI as compared to 1D post TBI. Histological analysis revealed improved neuron and oligodendrocyte survival and restored ileum tissue morphology at 7D post TBI in FMT treated animals. Microbiome analysis indicated decreased dysbiosis in FMT treated animals with an increase in multiple probiotic Lactobacilli species, associated with anti-inflammatory therapeutic effects, in the cecum of the FMT treated animals, while non-treated TBI animals showed an increase in pathogenic bacteria, associated with inflammation and disease such in feces. FMT mediated enhanced cellular and tissue recovery resulted in improved motor function including stride and step length and voluntary motor activity in FMT treated animals. Here we report for the first time in a highly translatable pediatric piglet TBI model, the potential of FMT treatment to significantly limit cellular and tissue damage leading to improved functional outcomes following a TBI.

ALCAM on human oligodendrocytes mediates CD4 T cell adhesion.

Multiple sclerosis is a chronic neuroinflammatory disorder characterized by demyelination, oligodendrocyte damage/loss and neuroaxonal injury in the context of immune cell infiltration in the CNS. No neuroprotective therapy is available to promote the survival of oligodendrocytes and protect their myelin processes in immune-mediated demyelinating diseases. Pro-inflammatory CD4 Th17 cells can interact with oligodendrocytes in multiple sclerosis and its animal model, causing injury to myelinating processes and cell death through direct contact. However, the molecular mechanisms underlying the close contact and subsequent detrimental interaction of Th17 cells with oligodendrocytes remain unclear. In this study we used single cell RNA sequencing, flow cytometry and immunofluorescence studies on CNS tissue from multiple sclerosis subjects, its animal model and controls to characterize the expression of cell adhesion molecules by mature oligodendrocytes. We found that a significant proportion of human and murine mature oligodendrocytes express melanoma cell adhesion molecule (MCAM) and activated leukocyte cell adhesion molecule (ALCAM) in multiple sclerosis, in experimental autoimmune encephalomyelitis and in controls, although their regulation differs between human and mouse. We observed that exposure to pro-inflammatory cytokines or to human activated T cells are associated with a marked downregulation of the expression of MCAM but not of ALCAM at the surface of human primary oligodendrocytes. Furthermore, we used in vitro live imaging, immunofluorescence and flow cytometry to determine the contribution of these molecules to Th17-polarized cell adhesion and cytotoxicity towards human oligodendrocytes. Silencing and blocking ALCAM but not MCAM limited prolonged interactions between human primary oligodendrocytes and Th17-polarized cells, resulting in decreased adhesion of Th17-polarized cells to oligodendrocytes and conferring significant protection of oligodendrocytic processes. In conclusion, we showed that human oligodendrocytes express MCAM and ALCAM, which are differently modulated by inflammation and T cell contact. We found that ALCAM is a ligand for Th17-polarized cells, contributing to their capacity to adhere and induce damage to human oligodendrocytes, and therefore could represent a relevant target for neuroprotection in multiple sclerosis.

Autophagy collaborates with apoptosis pathways to control oligodendrocyte number

Oligodendrocytes are the sole myelin-producing cells in the central nervous system. Oligodendrocyte number is tightly controlled across diverse brain regions to match local axon type and number, yet the underlying mechanisms remain unclear. Here, we show that autophagy, an evolutionarily conserved cellular process that promotes cell survival under physiological conditions, elicits premyelinating oligodendrocyte apoptosis during development. Autophagy flux is increased in premyelinating oligodendrocytes, and its genetic blockage causes ectopic oligodendrocyte survival throughout the entire brain. Autophagy functions cell autonomously in the premyelinating oligodendrocyte to trigger cell apoptosis, and it genetically interacts with the TFEB pathway to limit oligodendrocyte number across diverse brain regions. Our results provide invivo evidence showing that autophagy promotes apoptosis in mammalian cells under physiological conditions and reveal key intrinsic mechanisms governing oligodendrogenesis.

Opposite modulation of functional recovery following contusive spinal cord injury in mice with oligodendrocyte-selective deletions of Atf4 and Chop/Ddit3

The integrated stress response (ISR)-activated transcription factors ATF4 and CHOP/DDIT3 may regulate oligodendrocyte (OL) survival, tissue damage and functional impairment/recovery in white matter pathologies, including traumatic spinal cord injury (SCI). Accordingly, in OLs of OL-specific RiboTag mice, Atf4, Chop/Ddit3 and their downstream target gene transcripts were acutely upregulated at 2, but not 10, days post-contusive T9 SCI coinciding with maximal loss of spinal cord tissue. Unexpectedly, another, OL-specific upregulation of Atf4/Chop followed at 42 days post-injury. However, wild type versus OL-specific Atf4−/− or Chop−/− mice showed similar white matter sparing and OL loss at the injury epicenter, as well as unaffected hindlimb function recovery as determined by the Basso mouse scale. In contrast, the horizontal ladder test revealed persistent worsening or improvement of fine locomotor control in OL-Atf4−/− or OL-Chop−/− mice, respectively. Moreover, chronically, OL-Atf−/− mice showed decreased walking speed during plantar stepping despite greater compensatory forelimb usage. Therefore, ATF4 supports, while CHOP antagonizes, fine locomotor control during post-SCI recovery. No correlation between those effects and white matter sparing together with chronic activation of the OL ISR suggest that in OLs, ATF4 and CHOP regulate function of spinal cord circuitries that mediate fine locomotor control during post-SCI recovery.

Astragaloside IV ameliorates cognitive impairment and protects oligodendrocytes from antioxidative stress via regulation of the SIRT1/Nrf2 signaling pathway

Subcortical ischemic vascular dementia (SIVD), which is caused by chronic cerebral hypoperfusion, is a common subtype of vascular dementia, accompanied by white matter damage and cognitive impairment. Currently, there are no effective treatments for this condition. Oxidative stress is a key factor in the pathogenesis of white matter damage. Astragaloside IV (AS-IV), one of the main active components of astragaloside, has antioxidant properties and promotes cognitive improvement; however, its effect on SIVD and its potential mechanism remain unknown. We aimed to clarify whether AS-IV had a protective effect against SIVD injury caused by right unilateral common carotid artery occlusion and the underlying mechanism. The results showed that AS-IV treatment improved cognitive function and white matter damage, inhibited oxidative stress and glial cells activation, and promoted the survival of mature oligodendrocytes after chronic cerebral hypoperfusion. Moreover, the protein expression levels of NQO1, HO-1, SIRT1 and Nrf2 were increased by AS-IV treatment. However, pre-treatment with EX-527, a SIRT1-specific inhibitor, eliminated the beneficial effects of AS-IV. These results demonstrate that AS-IV plays a neuroprotective role in SIVD by suppressing oxidative stress and increasing the number of mature oligodendrocytes via the modulation of SIRT1/Nrf2 signaling. Our results support AS-IV as a potential therapeutic agent for SIVD.