Myelin Oligodendrocyte Research Articles

Myelination by signaling through Arf guanine nucleotide exchange factor.

During myelination, large quantities of proteins are synthesized and transported from the endoplasmic reticulum (ER)-trans-Golgi network (TGN) to their appropriate locations within the intracellular region and/or plasma membrane. It is widely believed that oligodendrocytes uptake neuronal signals from neurons to regulate the endocytosis- and exocytosis-mediated intracellular trafficking of major myelin proteins such as myelin-associated glycoprotein (MAG) and proteolipid protein 1 (PLP1). The small GTPases of the adenosine diphosphate (ADP) ribosylation factor (Arf) family constitute a large group of signal transduction molecules that act as regulators for intracellular signaling, vesicle sorting, or membrane trafficking in cells. Studies on mice deficient in Schwann cell-specific Arfs-related genes have revealed abnormal myelination formation in peripheral nerves, indicating that Arfs-mediated signaling transduction is required for myelination in Schwann cells. However, the complex roles in these events remain poorly understood. This review aims to provide an update on signal transduction, focusing on Arf and its activator ArfGEF (guanine nucleotide exchange factor for Arf) in oligodendrocytes and Schwann cells. Future studies are expected to provide important information regarding the cellular and physiological processes underlying the myelination of oligodendrocytes and Schwann cells and their function in modulating neural activity.

Trametinib, an anti-tumor drug, promotes oligodendrocytes generation and myelin formation.

Oligodendrocytes (OLs) are differentiated from oligodendrocyte precursor cells (OPCs) in the central nervous system (CNS). Demyelination is a common feature of many neurological diseases such as multiple sclerosis (MS) and leukodystrophies. Although spontaneous remyelination can happen after myelin injury, nevertheless, it is often insufficient and may lead to aggravated neurodegeneration and neurological disabilities. Our previous study has discovered that MEK/ERK pathway negatively regulates OPC-to-OL differentiation and remyelination in mouse models. To facilitate possible clinical evaluation, here we investigate several MEK inhibitors which have been approved by FDA for cancer therapies in both mouse and human OPC-to-OL differentiation systems. Trametinib, the first FDA approved MEK inhibitor, displays thebest effect in stimulating OL generation in vitro among the four MEK inhibitors examined. Trametinib also significantly enhances remyelination in both MOG-induced EAE model and LPC-induced focal demyelination model. More exciting, trametinib facilitates the generation of MBP+ OLs from human embryonic stem cells (ESCs)-derived OPCs. Mechanism study indicates that trametinib promotes OL generation by reducing E2F1 nuclear translocation and subsequent transcriptional activity. In summary, our studies indicate a similar inhibitory role of MEK/ERK in human and mouse OL generation. Targeting the MEK/ERK pathway might help to develop new therapies or repurpose existing drugs for demyelinating diseases.

Exploring Dimethylsulfoniopropionate as a potential treatment for Alzheimer's disease: A study using the 3 × Tg-AD mouse model

BackgroundAlzheimer's disease (AD), the most common neurodegenerative disorder, affects a broad spectrum of aging populations. AD is characterized by pathological amyloid-β (Aβ) plaques and neurofibrillary tangles, leading to neural degeneration and cognitive decline. The lack of effective treatments for AD highlights the urgent need for novel therapeutic agents, particularly in the early stages. Dimethylsulfoniopropionate (DMSP) is a natural marine compound with antioxidant and neuroprotective properties. However, studies on the efficacy of DMSP in the treatment of AD and its associated mechanisms are limited. PurposeThis study aimed to explore the therapeutic effects and mechanisms of action of DMSP as an AD treatment using a preclinical 3 × Tg-AD mouse model. MethodsThe research involved administering DMSP (7 μg/mL and 11 μg/mL in drinking water) to four-month-old 3 × Tg-AD mice consecutively for three months. The Y-maze test, novel object recognition test, and Morris water maze test were used to assess memory and learning ability. The relative expression levels and distribution of proteins relevant to Aβ and tau pathology, synapses, and glial cells were analyzed using western blotting and immunofluorescence assays. Additionally, proteomic and bioinformatics approaches were used to explore the potential targets of DMSP treatment. ResultsDMSP-treated AD mice showed significantly enhanced cognitive function, suggesting that DMSP mitigates memory and learning impairments in AD. Moreover, DMSP diminished the abnormal accumulation of Aβ and phosphorylated tau in both the cortex and hippocampus, which are crucial hallmarks of AD pathology. In addition to its neuroprotective properties, DMSP restored synaptic density and the expression of synaptic and neuronal proteins, which are essential for proper brain function. DMSP displayed anti-inflammatory properties, as evidenced by its ability to suppress inflammatory astrocytes and maintain microglial homeostasis. Notably, DMSP facilitated the maturation of oligodendrocytes (OLs) from oligodendrocyte progenitor cells (OPCs), a critical process in the development of the brain myelination architecture. Proteomic analysis revealed that DMSP positively influenced biological processes crucial for oligodendrocyte development, myelination, and axonal ensheathment, which are often compromised in patients with AD. Protein validation and brain tissue staining supported the role of DMSP in preserving myelin enrichment and sheath integrity. These therapeutic effects were largely attributed to the enhanced expression of myelin-associated glycoprotein (Mag) and tetraspanin Cd9. ConclusionOverall, our findings highlight DMSP as a promising novel therapeutic candidate for AD, offering multifaceted benefits in cognitive and memory enhancement, reduction of Aβ and tau pathology, neuronal synapse protection, anti-inflammatory effects, and myelin sheath restoration as an innovative target compared to other studies. In addition to being a potentially effective treatment for AD, DMSP may also have the potential to address other neurodegenerative diseases that are closely associated with myelin impairment.

Antagonistic actions of PAK1 and NF2/Merlin drive myelin membrane expansion in oligodendrocytes.

In the central nervous system, the formation of myelin by oligodendrocytes (OLs) relies on the switch from the polymerization of the actin cytoskeleton to its depolymerization. The molecular mechanisms that trigger this switch have yet to be elucidated. Here, we identified P21-activated kinase 1 (PAK1) as a major regulator of actin depolymerization in OLs. Our results demonstrate that PAK1 accumulates in OLs in a kinase-inhibited form, triggering actin disassembly and, consequently, myelin membrane expansion. Remarkably, proteomic analysis of PAK1 binding partners enabled the identification of NF2/Merlin as its endogenous inhibitor. Our findings indicate that Nf2 knockdown in OLs results in PAK1 activation, actin polymerization, and a reduction in OL myelin membrane expansion. This effect is rescued by treatment with a PAK1 inhibitor. We also provide evidence that the specific Pak1 loss-of-function in oligodendroglia stimulates the thickening of myelin sheaths in vivo. Overall, our data indicate that the antagonistic actions of PAK1 and NF2/Merlin on the actin cytoskeleton of the OLs are critical for proper myelin formation. These findings have broad mechanistic and therapeutic implications in demyelinating diseases and neurodevelopmental disorders.

Fibulin-2 is an extracellular matrix inhibitor of oligodendrocytes relevant to multiple sclerosis.

Impairment of oligodendrocytes and myelin contributes to neurological disorders including multiple sclerosis (MS), stroke, and Alzheimer's disease. Regeneration of myelin (remyelination) decreases the vulnerability of demyelinated axons, but this repair process commonly fails with disease progression. A contributor to inefficient remyelination is the altered extracellular matrix (ECM) in lesions, which remains to be better defined. We have identified fibulin-2 (FBLN2) as a highly upregulated ECM component in lesions of MS and stroke and in proteome databases of Alzheimer's disease and traumatic brain injury. Focusing on MS, the inhibitory role of FBLN2 was suggested in the experimental autoimmune encephalomyelitis (EAE) model, in which genetic FBLN2 deficiency improved behavioral recovery by promoting the maturation of oligodendrocytes and enhancing remyelination. Mechanistically, when oligodendrocyte progenitors were cultured in differentiation medium, FBLN2 impeded their maturation into oligodendrocytes by engaging the Notch pathway, leading to cell death. Adeno-associated virus deletion of FBLN2 in astrocytes improved oligodendrocyte numbers and functional recovery in EAE and generated new myelin profiles after lysolecithin-induced demyelination. Collectively, our findings implicate FBLN2 as a hitherto unrecognized injury-elevated ECM, and a therapeutic target, that impairs oligodendrocyte maturation and myelin repair.

Human endogenous retrovirus W in multiple sclerosis: transcriptional activity is associated with decline in oligodendrocyte proportions in the white matter of the brain.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease. One of the basic mechanisms in this disease is the autoimmune response against the myelin sheet leading to axonal damage. There is strong evidence showing that this response is regulated by both genetic and environmental factors. In addition, the role of viruses has been extensively studied, especially in the case of human endogenous retroviruses (HERVs). However, although several associations with MS susceptibility, especially in the case of HERV-W family have been observed, the pathogenic mechanisms have remained enigmatic. To clarify these HERV-mediated mechanisms as well as the responsible HERV-W loci, we utilized RNA sequencing data obtained from the white matter of the brain of individuals with and without MS. CIBERSORTx tool was applied to estimate the proportions of neuronal, glial, and endothelial cells in the brain. In addition, the transcriptional activity of 215 HERV-W loci were analyzed. The results indicated that 65 HERV-W loci had detectable expression, of which 14 were differentially expressed between MS and control samples. Of these, 12 HERV-W loci were upregulated in MS. Expression levels of the 8 upregulated HERV-W loci had significant negative correlation with estimated oligodendrocyte proportions, suggesting that they are associated with the dynamics of oligodendrocyte generation and/or maintenance. Furthermore, Gene Set Enrichment Analysis (GSEA) results indicated that expression levels of three upregulated HERV-W loci: 2p16.2, 2q13, and Xq13.3, are associated with suppression of oligodendrocyte development and myelination. Taken together, these data suggest new HERV-W loci candidates that might take part in MS pathogenesis.

Signaling of GPR17 in Hepatic and Renal Tissues

G protein-coupled receptors (GPCRs) are the largest class of proteins in the human body and are considered to be excellent targets for drug discovery. However, the vast majority of GPCRs are understudied. Using a large-scale TaqMan array screen on both male and female C57BL6 murine livers, we identified GPR17 as one of the most highly expressed orphan receptors within the liver (ΔCt = 19.9, normalized to GAPDH). GPR17 expression in the liver was confirmed using reverse transcriptase polymerase chain reaction (RT-PCR) and was also identified in murine whole kidney from both males and females indicating that GPR17 RNA expression is not sex-dependent. While GPR17 has known roles in oligodendrocyte maturation and myelination in the central nervous system, its functions within the liver and kidney are undetermined. To investigate its physiological functions, we started by uncovering its localization within the liver and kidney and identifying its ligand profile. A series of RNAScope in-situ hybridization assays were performed to localize GPR17 within hepatic tissue. Gpr17 mRNA was found within hepatocytes indicating that its highest expression is in the parenchymal cells of the liver. To identify possible activators for GPR17, we cloned the coding region into both flag-tagged PME18s and the Presto-Tango vectors. Live-cell surface labeling of HEK293T expressing the GPR17 constructs confirmed robust surface expression on the plasma membrane facilitating ligand screening. GPR17 downstream signaling has yet to be studied. Thus, we used the PRESTO-TANGO assay, an exogenous chemical ligand screening assay that relies on a luminescence readout to indicate -arrestin recruitment and receptor activation. A large, non-biased chemical screen of over 500 physiological compounds was tested for activation of GPR17. To date, we identified seven exogenous activators of GPR17: 3-[methyl(1,2,3,4- tetrahydronaphthalen-2-yl)amino]pyrazine-2-carbonitrile, 4-(4-fluorophenyl)-5-methyl-N-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)thiophene-2-carboxamide,({1-[(2-chlorophenyl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}methyl)(methyl)[(1-methyl-1H-imidazol-2-yl)methyl]amine,N,N-dimethyl-6-[(5-phenyl-1,3-oxazol-2-yl)methyl]-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-amine,4-phenyl-1-[6-(pyrrolidin-1-yl)-9H-purin-9-yl]butan-2-ol, 2-(3-fluorophenyl)-3-methyl-1-{[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl}pyrrolidine, and 2,6,6-trimethyl-N-({2-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrimidin-6-yl}methyl)-4,5,6,7-tetrahydro-1-benzofuran-4-amine. Ongoing studies are aimed at narrowing down the in vivo activators of GPR17 to ultimately shed light on the physiological functions that this receptor plays in the kidney and liver. NIH/NCATS. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A protective effect of lower MHC-II expression in MOGAD

Myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) is a demyelinating central nervous system disorder. We aimed to uncover immune pathways altered in MOGAD to predict disease progression. Using nanostring nCounter technology, we analyzed immune gene expression in PBMCs from MOGAD patients and compare it with healthy controls (HCs). We found 35 genes that distinguished MOGAD patients and HCs. We then validated those results in a larger cohort including MS and NMOSD patients. Expressions of HLA-DRA was significantly lower in MOGAD patients. This reduction in HLA-DRA, correlated with a monophasic disease course and greater brain volume, enhancing our ability to predict MOGAD progression.

Pathophysiology in cortico-amygdala circuits and excessive aversion processing: the role of oligodendrocytes and myelination.

Stress-related psychiatric illnesses, such as major depressive disorder, anxiety and post-traumatic stress disorder, present with alterations in emotional processing, including excessive processing of negative/aversive stimuli and events. The bidirectional human/primate brain circuit comprising anterior cingulate cortex and amygdala is of fundamental importance in processing emotional stimuli, and in rodents the medial prefrontal cortex-amygdala circuit is to some extent analogous in structure and function. Here, we assess the comparative evidence for: (i) Anterior cingulate/medial prefrontal cortex<->amygdala bidirectional neural circuits as major contributors to aversive stimulus processing; (ii) Structural and functional changes in anterior cingulate cortex<->amygdala circuit associated with excessive aversion processing in stress-related neuropsychiatric disorders, and in medial prefrontal cortex<->amygdala circuit in rodent models of chronic stress-induced increased aversion reactivity; and (iii) Altered status of oligodendrocytes and their oligodendrocyte lineage cells and myelination in anterior cingulate/medial prefrontal cortex<->amygdala circuits in stress-related neuropsychiatric disorders and stress models. The comparative evidence from humans and rodents is that their respective anterior cingulate/medial prefrontal cortex<->amygdala circuits are integral to adaptive aversion processing. However, at the sub-regional level, the anterior cingulate/medial prefrontal cortex structure-function analogy is incomplete, and differences as well as similarities need to be taken into account. Structure-function imaging studies demonstrate that these neural circuits are altered in both human stress-related neuropsychiatric disorders and rodent models of stress-induced increased aversion processing. In both cases, the changes include altered white matter integrity, albeit the current evidence indicates that this is decreased in humans and increased in rodent models. At the cellular-molecular level, in both humans and rodents, the current evidence is that stress disorders do present with changes in oligodendrocyte lineage, oligodendrocytes and/or myelin in these neural circuits, but these changes are often discordant between and even within species. Nonetheless, by integrating the current comparative evidence, this review provides a timely insight into this field and should function to inform future studies-human, monkey and rodent-to ascertain whether or not the oligodendrocyte lineage and myelination are causally involved in the pathophysiology of stress-related neuropsychiatric disorders.

Vesicle Fusion in Oligodendrocyte Maturation and Myelination.

Vesicle Fusion in Oligodendrocyte Maturation and Myelination.

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

JOURNAL/nrgr/04.03/01300535-202507000-00024/figure1/v/2024-09-09T124005Z/r/image-tiff 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.

Novel Genetic Variants Distinguishing Myelin Oligodendrocyte Glycoprotein-IgG-Positive From Myelin Oligodendrocyte Glycoprotein-IgG-Negative Pediatric Acute Disseminated Encephalomyelitis in Northern China

BackgroundAcute disseminated encephalomyelitis (ADEM) is a common phenotype in children with myelin oligodendrocyte glycoprotein IgG (MOG-IgG)-associated disease. We aimed to identify novel genetic variants that distinguish children with MOG-IgG-positive ADEM (MOG-IgG+ ADEM) from children with MOG-IgG-negative ADEM (MOG-IgG− ADEM) using whole exome sequencing (WES) analysis. MethodsWe conducted a two-stage study design. First, we performed WES on five patients with MOG-IgG+ ADEM and five patients with MOG-IgG− ADEM. Following bioinformatics analysis, the candidate variant list was constructed. Second, 29 children with MOG-IgG+ ADEM and 27 children with MOG-IgG− ADEM, together with discovery cohort, were genotyped to identify the novel variants. ResultsWES resulted in 33,999 variants, and 5388 nonsynonymous variants were selected for downstream analysis. In total, 118 protein-affecting variants that were significantly different between the two groups were identified. Together with the five variants extracted from the literature, 49 variants were selected as the candidate variant list for genotyping in the replication cohort. Finally, we identified three variants: rs11171951 in NACα, rs231775 in CTLA4, and rs11171951 in GOLGA5, which were significantly different between MOG-IgG+ ADEM and MOG-IgG− ADEM. Only rs12440118 in NACα remained significant after Bonferroni correction for multiple testing (Padj < 0.001). ConclusionsWe identified strong associations between NACα, CTLA4, and GOLGA5 variants and MOG-IgG+ ADEM in a Han Chinese population of Northern China, which may present novel genetic risk factor distinguishing patients with MOG-IgG+ ADEM from those with MOG-IgG− ADEM.

The Effects and Mechanism of Scutellaria baicalensis Georgi Stems and Leaves Flavonoids on Myelin Sheath Degeneration Induced by Composite Aβ in Rats.

Alzheimer's disease is a degenerative disease of the central nervous system, and its characteristic pathological changes are closely associated with Aβ deposition and neurofibrillary tangles. Many studies have found that malignant changes in the myelin sheath and oligodendrocyte (OL) are accompanied by the occurrence and development of AD. Therefore, any method that can resist myelin sheath and OL disorders may be a potential strategy for AD. To investigate the effects and mechanism of Scutellaria baicalensis Georgi stem and leaf flavonoids (SSFs) on the myelin sheath degeneration induced by Aβ25-35 combined with AlC13 and RHTGF-β1 (composite Aβ) in rats. A rat AD model was established by intracerebroventricular injection of composite Aβ. The Morris water maze was used to screen the memory impairment rat model. The successful model rats were divided into the model group and the 35, 70, and 140 mg/kg SSFS groups. The myelin sheath changes in the cerebral cortex were observed with an electron microscope. The expression of the oligodendrocyte- specific protein claudin 11 was detected with immunohistochemistry. The protein expression levels of myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein (MAG) and myelin basic protein (MBP), sphingomyelin synthase-1 (SMS1), and sphingomyelinase-2 (SMPD2) were assayed by Western blotting. The intracerebroventricular injection of composite Aβ caused degeneration of the myelin sheath structure and was accompanied by the decreased claudin 11, MOG, MAG, MBP, and SMS1, and increased SMPD2 protein expression in the cerebral cortex. However, 35, 70, and 140 mg/kg SSFs can differentially ameliorate the above abnormal changes induced by composite Aβ. SSFs can alleviate myelin sheath degeneration and increase the protein expression of claudin 11, MOG, MAG, and MBP, and the effective mechanism may be related to the positive regulation of SMS1 and SMPD2 activities.

Dmd mdx mice have defective oligodendrogenesis, delayed myelin compaction and persistent hypomyelination.

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, resulting in the loss of dystrophin, a large cytosolic protein that links the cytoskeleton to extracellular matrix receptors in skeletal muscle. Aside from progressive muscle damage, many patients with DMD also have neurological deficits of unknown etiology. To investigate potential mechanisms for DMD neurological deficits, we assessed postnatal oligodendrogenesis and myelination in the Dmdmdx mouse model. In the ventricular-subventricular zone (V-SVZ) stem cell niche, we found that oligodendrocyte progenitor cell (OPC) production was deficient, with reduced OPC densities and proliferation, despite a normal stem cell niche organization. In the Dmdmdx corpus callosum, a large white matter tract adjacent to the V-SVZ, we also observed reduced OPC proliferation and fewer oligodendrocytes. Transmission electron microscopy further revealed significantly thinner myelin, an increased number of abnormal myelin structures and delayed myelin compaction, with hypomyelination persisting into adulthood. Our findings reveal alterations in oligodendrocyte development and myelination that support the hypothesis that changes in diffusion tensor imaging seen in patients with DMD reflect developmental changes in myelin architecture.

The myelination-associated G protein-coupled receptor 37 is regulated by Zfp488, Nkx2.2, and Sox10 during oligodendrocyte differentiation.

Oligodendrocyte differentiation and myelination in the central nervous system are controlled and coordinated by a complex gene regulatory network that contains several transcription factors, including Zfp488 and Nkx2.2. Despite the proven role in oligodendrocyte differentiation little is known about the exact mode of Zfp488 and Nkx2.2 action, including their target genes. Here, we used overexpression of Zfp488 and Nkx2.2 in differentiating CG4 cells to identify aspects of the oligodendroglial expression profile that depend on these transcription factors. Although both transcription factors are primarily described as repressors, the detected changes argue for an additional function as activators. Among the genes activated by both Zfp488 and Nkx2.2 was the G protein-coupled receptor Gpr37 that is important during myelination. In agreement with a positive effect on Gpr37 expression, downregulation of the G protein-coupled receptor was observed in Zfp488- and in Nkx2.2-deficient oligodendrocytes in the mouse. We also identified several potential regulatory regions of the Gpr37 gene. Although Zfp488 and Nkx2.2 both bind to one of the regulatory regions downstream of the Gpr37 gene in vivo, none of the regulatory regions was activated by either transcription factor alone. Increased activation by Zfp488 or Nkx2.2 was only observed in the presence of Sox10, a transcription factor continuously present in oligodendroglial cells. Our results argue that both Zfp488 and Nkx2.2 also act as transcriptional activators during oligodendrocyte differentiation and cooperate with Sox10 to allow the expression of Gpr37 as a modulator of the myelination process.

Oligodendrocyte progenitor cells' fate after neonatal asphyxia-Puzzling implications for the development of hypoxic-ischemic encephalopathy.

Premature birth or complications during labor can cause temporary disruption of cerebral blood flow, often followed by long-term disturbances in brain development called hypoxic-ischemic (HI) encephalopathy. Diffuse damage to the white matter is the most frequently detected pathology in this condition. We hypothesized that oligodendrocyte progenitor cell (OPC) differentiation disturbed by mild neonatal asphyxia may affect the viability, maturation, and physiological functioning of oligodendrocytes. To address this issue, we studied the effect of temporal HI in the in vivo model in P7 rats with magnetic resonance imaging (MRI), microscopy techniques and biochemical analyses. Moreover, we recreated the injury in vitro performing the procedure of oxygen-glucose deprivation on rat neonatal OPCs to determine its effect on cell viability, proliferation, and differentiation. In the in vivo model, MRI evaluation revealed changes in the volume of different brain regions, as well as changes in the directional diffusivity of water in brain tissue that may suggest pathological changes to myelinated neuronal fibers. Hypomyelination was observed in the cortex, striatum, and CA3 region of the hippocampus. Severe changes to myelin ultrastructure were observed, including delamination of myelin sheets. Interestingly, shortly after the injury, an increase in oligodendrocyte proliferation was observed, followed by an overproduction of myelin proteins 4 weeks after HI. Results verified with the in vitro model indicate, that in the first days after damage, OPCs do not show reduced viability, intensively proliferate, and overexpress myelin proteins and oligodendrocyte-specific transcription factors. In conclusion, despite the increase in oligodendrocyte proliferation and myelin protein expression after HI, the production of functional myelin sheaths in brain tissue is impaired. Presented study provides a detailed description of oligodendrocyte pathophysiology developed in an effect of HI injury, resulting in an altered CNS myelination. The described models may serve as useful tools for searching and testing effective of effective myelination-supporting therapies for HI injuries.

Metabolomics-Based Effects of a Natural Product on Remyelination After Cerebral Ischemia Injury Via GABABR–pCREB–BDNF Pathway

Background Yi-Qi-Tong-Luo Granules (YQTLs) is a natural compound of Traditional Chinese Medicine authorized by China Food and Drug Administration (CFDA). These granules are employed in the convalescent stage of cerebral infarction and render notable clinical efficacy. This study aims to uncover the underlying mechanisms of YQTLs on remyelination after cerebral ischemia injury. Materials and Methods We established cerebral ischemia model in rats using microsphere-induced multiple cerebral infarction (MCI). We evaluated the pharmacological effects of YQTLs on MCI rats, through Morri’s water maze test, open field test, hematoxylin and eosin staining, and glycine silver immersion. We employed liquid chromatography mass spectrometry metabolomics to identify differential metabolites. Enzyme-linked immunosorbent assay was utilized to measure the release of neurotrophins, while immunofluorescence staining was used to assess oligodendrocyte precursor cells differences and myelin regeneration. We used Western blotting to validate the protein expression of remyelination-associated signaling pathways. Results YQTLs significantly improves cognitive function following cerebral ischemia injury. Pathological tissue staining revealed that YQTLs administration inhibits neuronal denaturation and neurofibrillary tangles. We identified 141 differential metabolites among the sham, MCI, and YQTLs-treated MCI groups. Among these metabolites, neurotransmitters were identified, and notably, gamma-aminobutyric acid (GABA) showed marked improvement in the YQTLs group. The induction of neurotrophins, such as brain-derived neurotrophic factor (BDNF) and PDGFAA, upregulation of olig2 and MBP expression, and promotion of remyelination were evident in YQTLs-treated MCI groups. Gamma-aminobutyric acid B receptors (GABABR), pERK/extracellular regulated MAP kinase, pAKT/protein kinase B, and pCREB/cAMP response element-binding were upregulated following YQTLs treatment. Conclusion YQTLs enhance the binding of GABA to GABABR, thereby activating the pCREB/BDNF signaling pathway, which in turn increases the expression of downstream myelin-associated proteins and promotes remyelination and cognitive function.

ITPR2 Mediated Calcium Homeostasis in Oligodendrocytes is Essential for Myelination and Involved in Depressive-Like Behavior in Adolescent Mice.

Ca2+ signaling is essential for oligodendrocyte (OL) development and myelin formation. Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2) is an endoplasmic reticulum calcium channel and shows stage-dependent high levels in postmitotic oligodendrocyte precursor cells (OPCs). The role and potential mechanism of ITPR2 in OLs remain unclear. In this study, it is revealed that loss of Itpr2 in OLs disturbs Ca2+ homeostasis and inhibits myelination in adolescent mice. Animals with OL-specific deletion of Itpr2 exhibit anxiety/depressive-like behaviors and manifest with interrupted OPC proliferation, leading to fewer mature OLs in the brain. Detailed transcriptome profiling and signal pathway analysis suggest that MAPK/ERK-CDK6/cyclin D1 axis underlies the interfered cell cycle progression in Itpr2 ablated OPCs. Besides, blocking MAPK/ERK pathway significantly improves the delayed OPC differentiation and myelination in Itpr2 mutant. Notably, the resting [Ca2+]i is increased in Itpr2 ablated OPCs, with the elevation of several plasma calcium channels. Antagonists against these plasma calcium channels can normalize the resting [Ca2+]i level and enhance lineage progression in Itpr2-ablated OPCs. Together, the findings reveal novel insights for calcium homeostasis in manipulating developmental transition from OPCs to pre-OLs; additionally, the involvement of OLs-originated ITPR2 in depressive behaviors provides new therapeutic strategies to alleviate myelin-associated psychiatric disorders.

Ageing impairs the regenerative capacity of regulatory T cells in mouse central nervous system remyelination

Myelin regeneration (remyelination) is essential to prevent neurodegeneration in demyelinating diseases such as Multiple Sclerosis, however, its efficiency declines with age. Regulatory T cells (Treg) recently emerged as critical players in tissue regeneration, including remyelination. However, the effect of ageing on Treg-mediated regenerative processes is poorly understood. Here, we show that expansion of aged Treg does not rescue age-associated remyelination impairment due to an intrinsically diminished capacity of aged Treg to promote oligodendrocyte differentiation and myelination in male and female mice. This decline in regenerative Treg functions can be rescued by a young environment. We identified Melanoma Cell Adhesion Molecule 1 (MCAM1) and Integrin alpha 2 (ITGA2) as candidates of Treg-mediated oligodendrocyte differentiation that decrease with age. Our findings demonstrate that ageing limits the neuroregenerative capacity of Treg, likely limiting their remyelinating therapeutic potential in aged patients, and describe two mechanisms implicated in Treg-driven remyelination that may be targetable to overcome this limitation.

Coexpression network analysis of the adult brain sheds light on the pathogenic mechanism of DDR1 in schizophrenia and bipolar disorder

DDR1 has been linked to schizophrenia (SCZ) and bipolar disorder (BD) in association studies. DDR1 encodes 58 distinct transcripts, which can be translated into five isoforms (DDR1a-e) and are expressed in the brain. However, the transcripts expressed in each brain cell type, their functions and their involvement in SCZ and BD remain unknown. Here, to infer the processes in which DDR1 transcripts are involved, we used transcriptomic data from the human brain dorsolateral prefrontal cortex of healthy controls (N = 936) and performed weighted gene coexpression network analysis followed by enrichment analyses. Then, to explore the involvement of DDR1 transcripts in SCZ (N = 563) and BD (N = 222), we studied the association of coexpression modules with disease and performed differential expression and transcript significance analyses. Some DDR1 transcripts were distributed across five coexpression modules identified in healthy controls (MHC). MHC1 and MHC2 were enriched in the cell cycle and proliferation of astrocytes and OPCs; MHC3 and MHC4 were enriched in oligodendrocyte differentiation and myelination; and MHC5 was enriched in neurons and synaptic transmission. Most of the DDR1 transcripts associated with SCZ and BD pertained to MHC1 and MHC2. Altogether, our results suggest that DDR1 expression might be altered in SCZ and BD via the proliferation of astrocytes and OPCs, suggesting that these processes are relevant in psychiatric disorders.