Response Of Oligodendrocytes Research Articles

Myelin ensheathment and drug responses of oligodendrocytes are modulated by stiffness of artificial axons.

Myelination is a key biological process wherein glial cells such as oligodendrocytes wrap myelin around neuronal axons, forming an insulative sheath that accelerates signal propagation down the axon. A major obstacle to understanding myelination is the challenge of visualizing and reproducibly quantifying this inherently three-dimensional process in vitro. To this end, we previously developed artificial axons (AAs), a biocompatible platform consisting of 3D-printed hydrogel-based axon mimics designed to more closely recapitulate the micrometer-scale diameter and sub-kilopascal mechanical stiffness of biological axons. First, we present our platform for fabricating AAs with tunable axon diameter, stiffness, and inter-axonal spacing. Second, we demonstrate that increasing the Young's modulus E or stiffness of polymer comprising the AAs increases the extent of myelin ensheathment by rat oligodendrocytes. Third, we demonstrate that the responses of oligodendrocytes to pro-myelinating compounds are also dependent on axon stiffness, which can affect compounds efficacy and the relative ranking. These results reinforce the importance of studying myelination in mechanically representative environments, and highlight the importance of considering biophysical cues when conducting drug screening studies.

From BBB to PPP: Bioenergetic requirements and challenges for oligodendrocytes in health and disease.

Mature myelinating oligodendrocytes, the cells that produce the myelin sheath that insulates axons in the central nervous system, have distinct energetic and metabolic requirements compared to neurons. Neurons require substantial energy to execute action potentials, while the energy needs of oligodendrocytes are directed toward building the lipid-rich components of myelin and supporting neuronal metabolism by transferring glycolytic products to axons as additional fuel. The utilization of energy metabolites in the brain parenchyma is tightly regulated to meet the needs of different cell types. Disruption of the supply of metabolites can lead to stress and oligodendrocyte injury, contributing to various neurological disorders, including some demyelinating diseases. Understanding the physiological properties, structures, and mechanisms involved in oligodendrocyte energy metabolism, as well as the relationship between oligodendrocytes and neighboring cells, is crucial to investigate the underlying pathophysiology caused by metabolic impairment in these disorders. In this review, we describe the particular physiological properties of oligodendrocyte energy metabolism and the response of oligodendrocytes to metabolic stress. We delineate the relationship between oligodendrocytes and other cells in the context of the neurovascular unit, and the regulation of metabolite supply according to energetic needs. We focus on the specific bioenergetic requirements of oligodendrocytes and address the disruption of metabolic energy in demyelinating diseases. We encourage further studies to increase understanding of the significance of metabolic stress on oligodendrocyte injury, to support the development of novel therapeutic approaches for the treatment of demyelinating diseases.

Single-nucleus RNA sequencing of human periventricular white matter in vascular dementia.

Vascular dementia (VaD) refers to a variety of dementias driven by cerebrovascular disease and is the second leading cause of dementia globally. VaD may be caused by ischemic strokes, intracerebral hemorrhage, and/or cerebral small vessel disease, commonly identified as white matter hyperintensities on MRI. The mechanisms underlying these white matter lesions in the periventricular brain are poorly understood. In this study we perform an extensive transcriptomic analysis on human postmortem periventricular white matter lesions in patients with VaD with the goal of identifying molecular pathways in the disease. We find increased cellular stress responses in astrocytes, oligodendrocytes, and oligodendrocyte precursor cells as well as transcriptional and translational repression in microglia in our dataset. We show that several genes identified by GWAS as being associated with white matter disease are differentially expressed in cells in VaD. Finally, we compare our dataset to an independent snRNAseq dataset of PVWM in VaD and a scRNAseq dataset on human iPSC-derived microglia exposed to oxygen glucose deprivation (OGD). We identify the increase of the heat shock protein response as a conserved feature of VaD across celltypes and show that this increase is not linked to OGD exposure. Overall, our study is the first to show that increased heat shock protein responses are a common feature of lesioned PVWM in VaD and may represent a potential therapeutic target.

Tlr7 drives sex differences in age- and Alzheimer's disease-related demyelination.

Alzheimer's disease (AD) and other age-related disorders associated with demyelination exhibit sex differences. In this work, we used single-nuclei transcriptomics to dissect the contributions of sex chromosomes and gonads in demyelination and AD. In a mouse model of demyelination, we identified the roles of sex chromosomes and gonads in modifying microglia and oligodendrocyte responses before and after myelin loss. In an AD-related mouse model expressing APOE4, XY sex chromosomes heightened interferon (IFN) response and tau-induced demyelination. The X-linked gene, Toll-like receptor 7 (Tlr7), regulated sex-specific IFN response to myelin. Deletion of Tlr7 dampened sex differences while protecting against demyelination. Administering TLR7 inhibitor mitigated tau-induced motor impairment and demyelination in male mice, indicating that Tlr7 plays a role in the male-biased type I Interferon IFN response in aging- and AD-related demyelination.

Abstract 4121198: Structural Network Alterations After Cardiopulmonary Bypass In a Juvenile Porcine Model

Background: Cardiopulmonary bypass (CPB) can trigger inflammatory and oxidative stresses in the developing brain. Clinical studies showed altered brain network structure in children after infant cardiac surgery. However, the impact of CPB on structural connectivity remains poorly understood. This study aims to determine the effects of CPB on structural connectivity and underlying cellular events using a juvenile porcine model. Methods: CPB (150 min total) was performed on 2-week-old Yorkshire piglets. High-resolution diffusion tensor imaging (DTI) and neurite orientation dispersion and density (NODDI) imaging were performed 4 weeks post-CPB in a total of 12 animals (Control; n=7, CPB; n=5). Structural connectivity assay together with histological analysis was conducted to assess the brain network organization. Results: Our network analysis (Image 1) revealed a CPB-induced reduction of structural connections in particular nodes, such as in the anterior prefrontal cortex (APC), primary somatosensory cortex, substantia nigra (SN), and globus pallidus (GP). In contrast, there was an increase in the premotor cortex (PreMC), primary motor cortex (PriMC), dorsal posterior cingulate cortex (DPCC), and somatosensory cortex (SAC). Three-dimensional images were generated based on these altered nodes, and tractography was generated to indicate changed fiber tracking (Image 2). We found reduced network connections between the basal ganglia and frontal cortex, and increased connections between the motor and posterior region. DTI and NODDI indicated that microstructures of the superior corona radiata (SCR), internal capsule (PLIC), and anterior prefrontal (AP-WM), motor (PreM-/PriM-WM), and somatosensory white matter (SA-WM) were significantly altered after CPB (Image 3). While Iba1+ microglia was activated across all brain regions after CPB (P<.05), CPB-induced oligodendrocyte immatureness was identified in the WMs involved in APC-SN and APC-GP pathways (P<.05). Notably, CPB increased the number of mature oligodendrocytes in motor and SA-WMs (P<.05) where structural connections were increased after CPB. In addition, we found SN dopaminergic neuron injury after CPB (P<.05). Conclusion: CPB altered structural network organization in the developing brain. Spatial differences in oligodendrocyte responses and susceptibility of specific subpopulations of neurons may contribute to the unique connectivity alterations observed after CPB.

Uncovering Plaque-Glia Niches in Human Alzheimer's Disease Brains Using Spatial Transcriptomics.

Amyloid-beta (Aβ) plaques and surrounding glial activation are prominent histopathological hallmarks of Alzheimer's Disease (AD). However, it is unclear how Aβ plaques interact with surrounding glial cells in the human brain. Here, we applied spatial transcriptomics (ST) and immunohistochemistry (IHC) for Aβ, GFAP, and IBA1 to acquire data from 258,987 ST spots within 78 postmortem brain sections of 21 individuals. By coupling ST and adjacent-section IHC, we showed that low Aβ spots exhibit transcriptomic profiles indicative of greater neuronal loss than high Aβ spots, and high-glia spots present transcriptomic changes indicative of more significant inflammation and neurodegeneration. Furthermore, we observed that this ST glial response bears signatures of reported mouse gene modules of plaque-induced genes (PIG), oligodendrocyte (OLIG) response, disease-associated microglia (DAM), and disease-associated astrocytes (DAA), as well as different microglia (MG) states identified in human AD brains, indicating that multiple glial cell states arise around plaques and contribute to local immune response. We then validated the observed effects of Aβ on cell apoptosis and plaque-surrounding glia on inflammation and synaptic loss using IHC. In addition, transcriptomic changes of iPSC-derived microglia-like cells upon short-interval Aβ treatment mimic the ST glial response and mirror the reported activated MG states. Our results demonstrate an exacerbation of synaptic and neuronal loss in low-Aβ or high-glia areas, indicating that microglia response to Aβ-oligomers likely initiates glial activation in plaque-glia niches. Our study lays the groundwork for future pathology genomics studies, opening the door for investigating pathological heterogeneity and causal effects in neurodegenerative diseases.

Early depletion of gut microbiota shape oligodendrocyte response after traumatic brain injury

White matter injury (WMI) is thought to be a major contributor to long-term cognitive dysfunctions after traumatic brain injury (TBI). This damage occurs partly due to apoptotic death of oligodendrocyte lineage cells (OLCs) after the injury, triggered directly by the trauma or in response to degenerating axons. Recent research suggests that the gut microbiota modulates the inflammatory response through the regulation of peripheral immune cell infiltration after TBI. Additionally, T-cells directly impact OLCs differentiation and proliferation. Therefore, we hypothesized that the gut microbiota plays a critical role in regulating the OLC response to WMI influencing T-cells differentiation and activation. Gut microbial depletion early after TBI chronically reduced re-myelination, acutely decreased OLCs proliferation, and was associated with increased myelin debris accumulation. Surprisingly, the absence of T-cells in gut microbiota depleted mice restored OLC proliferation and remyelination after TBI. OLCs co-cultured with T-cells derived from gut microbiota depleted mice resulted in impaired proliferation and increased expression of MHC-II compared with T cells from control-injured mice. Furthermore, MHC-II expression in OLCs appears to be linked to impaired proliferation under gut microbiota depletion and TBI conditions. Collectively our data indicates that depletion of the gut microbiota after TBI impaired remyelination, reduced OLCs proliferation with concomitantly increased OLC MHCII expression, and required the presence of T cells. This data suggests that T cells are an important mechanistic link by which the gut microbiota modulate the oligodendrocyte response and white matter recovery after TBI.

Thyroid hormone T4 mitigates traumatic brain injury in mice by dynamically remodeling cell type specific genes, pathways, and networks in hippocampus and frontal cortex

The complex pathology of mild traumatic brain injury (mTBI) is a main contributor to the difficulties in achieving a successful therapeutic regimen. Thyroxine (T4) administration has been shown to prevent the cognitive impairments induced by mTBI in mice but the mechanism is poorly understood. To understand the underlying mechanism, we carried out a single cell transcriptomic study to investigate the spatiotemporal effects of T4 on individual cell types in the hippocampus and frontal cortex at three post-injury stages in a mouse model of mTBI. We found that T4 treatment altered the proportions and transcriptomes of numerous cell types across tissues and timepoints, particularly oligodendrocytes, astrocytes, and microglia, which are crucial for injury repair. T4 also reversed the expression of mTBI-affected genes such as Ttr, mt-Rnr2, Ggn12, Malat1, Gnaq, and Myo3a, as well as numerous pathways such as cell/energy/iron metabolism, immune response, nervous system, and cytoskeleton-related pathways. Cell-type specific network modeling revealed that T4 mitigated select mTBI-perturbed dynamic shifts in subnetworks related to cell cycle, stress response, and RNA processing in oligodendrocytes. Cross cell-type ligand-receptor networks revealed the roles of App, Hmgb1, Fn1, and Tnf in mTBI, with the latter two ligands having been previously identified as TBI network hubs. mTBI and/or T4 signature genes were enriched for human genome-wide association study (GWAS) candidate genes for cognitive, psychiatric and neurodegenerative disorders related to mTBI. Our systems-level single cell analysis elucidated the temporal and spatial dynamic reprogramming of cell-type specific genes, pathways, and networks, as well as cell-cell communications as the mechanisms through which T4 mitigates cognitive dysfunction induced by mTBI.

BIN1K358R suppresses glial response to plaques in mouse model of Alzheimer's disease.

The BIN1 coding variant rs138047593 (K358R) is linked to Late-Onset Alzheimer's Disease (LOAD) via targeted exome sequencing. To elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1K358R knock-in mice using CRISPR/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer's pathology. The presence of the BIN1K358R variant leads to increased cerebral amyloid deposition, with a dampened response of astrocytes and oligodendrocytes, but not microglia, at both the cellular and transcriptional levels. This correlates with decreased neurofilament light chain in both plasma and brain tissue. Synaptic densities are significantly increased in both wild-type and 5xFAD backgrounds homozygous for the BIN1K358R variant. The BIN1 K358R variant modulates amyloid pathology in 5xFAD mice, attenuates the astrocytic and oligodendrocytic responses to amyloid plaques, decreases damage markers, and elevates synaptic densities. BIN1 rs138047593 (K358R) coding variant is associated with increased risk of LOAD. BIN1 K358R variant increases amyloid plaque load in 12-month-old 5xFAD mice. BIN1 K358R variant dampens astrocytic and oligodendrocytic response to plaques. BIN1 K358R variant decreases neuronal damage in 5xFAD mice. BIN1 K358R upregulates synaptic densities and modulates synaptic transmission.

Diverse Responses of Oligodendrocytes to Different FGF-Family Members: Uncoupling Structure-Function Relationship Within FGF Subfamilies.

The fifteen canonical paracrine fibroblast growth factors (FGFs) are organized in five subfamilies that interact with four FGF-receptors (FGFRs) and heparan sulfate proteoglycan (HSPG) co-receptors. Many of these FGFs are expressed in CNS regions where oligodendrocyte (OL) progenitors originate, migrate or differentiate. FGF2 (basic FGF) is considered a prototype FGF and the information about the effects of FGF signaling on OL-lineage cells has evolved largely from the study of FGF2. However, other FGFs from four subfamilies ((FGF1 (FGF1,-2), FGF4 (FGF4,-5,-6), FGF8 (FGF8,-17,-18) and FGF9 (FGF9,-16,-20)) that can interact with the isoforms of FGFRs expressed in OL-lineage cells may also play important roles. We previously reported OL-responses to FGF8 family members. Here, we investigate the effects of members of the FGF1,-4, and -9 subfamilies on proliferation and differentiation of OL progenitors (OPCs), and on cell cycle re-entry and down-regulation of myelin proteins by mature OLs. We found that while FGF2 induced all these responses strongly, FGF4,-6,-9 could do so only transiently and in the presence of exogenous HSPGs, and that FGF5,-16,-20 could not do so even in the presence of heparin or at higher concentrations. Furthermore, we noted that structurally similar FGFs within subfamilies did not always show similarities in their biological effects on OL-lineage cells. Taken together, these studies reveal that FGFs differ in the way they regulate the OL-lineage cells, emphasizes the selectivity and importance of HSPGs as FGF co-receptors in OL-lineage cells and suggests that structural similarity among FGF-subfamily members may not always predict their overlapping biological functions.

REDOX Balance in Oligodendrocytes Is Important for Zebrafish Visual System Regeneration.

Zebrafish (Danio rerio) present continuous growth and regenerate many parts of their body after an injury. Fish oligodendrocytes, microglia and astrocytes support the formation of new connections producing effective regeneration of the central nervous system after a lesion. To understand the role of oligodendrocytes and the signals that mediate regeneration, we use the well-established optic nerve (ON) crush model. We also used sox10 fluorescent transgenic lines to label fully differentiated oligodendrocytes. To quench the effect of reactive oxygen species (ROS), we used the endogenous antioxidant melatonin. Using these tools, we measured ROS production by flow cytometry and explored the regeneration of the optic tectum (OT), the response of oligodendrocytes and their mitochondria by confocal microscopy and Western blot. ROS are produced by oligodendrocytes 3 h after injury and JNK activity is triggered. Concomitantly, there is a decrease in the number of fully differentiated oligodendrocytes in the OT and in their mitochondrial population. By 24 h, oligodendrocytes partially recover. Exposure to melatonin blocks the changes observed in these oligodendrocytes at 3 h and increases their number and their mitochondrial populations after 24 h. Melatonin also blocks JNK upregulation and induces aberrant neuronal differentiation in the OT. In conclusion, a proper balance of ROS is necessary during visual system regeneration and exposure to melatonin has a detrimental impact.

Artificial axons as a biomimetic 3D myelination platform for the discovery and validation of promyelinating compounds

Multiple sclerosis (MS), a chronic neurodegenerative disease driven by damage to the protective myelin sheath, is currently incurable. Today, all clinically available treatments modulate the immune-mediated symptoms of the disease but they fail to stop neurodegeneration in many patients. Remyelination, the regenerative process of myelin repair by oligodendrocytes, which is considered a necessary step to protect demyelinated axons and stop neuronal death, is impaired in MS patients. One of the major obstacles to finding effective remyelinating drugs is the lack of biomimetic drug screening platforms that enable quantification of compounds’ potential to stimulate 3D myelination in the physiologically relevant axon-like environment. To address this need, we built a unique myelination drug discovery platform, by expanding our previously developed technology, artificial axons (AAs), which enables 3D-printing of synthetic axon mimics with the geometry and mechanical properties closely resembling those of biological axons. This platform allows for high-throughput phenotypic myelination assay based on quantification of 3D wrapping of myelin membrane around axons in response to compounds. Here, we demonstrate quantification of 3D myelin wrapping by rat oligodendrocytes around the axon mimics in response to a small library of known pro-myelinating compounds. This assay shows pro-myelinating activity for all tested compounds consistent with the published in vitro and in vivo data, demonstrating predictive power of AA platform. We find that stimulation of myelin wrapping by these compounds is dose-dependent, providing a facile means to quantify the compounds’ potency and efficacy in promoting myelin wrapping. Further, the ranking of relative efficacy among these compounds differs in this 3D axon-like environment as compared to a traditional oligodendrocyte 2D differentiation assay quantifying area of deposited myelin membrane. Together, we demonstrate that the artificial axons platform and associated phenotypic myelin wrapping assay afford direct evaluation of myelin wrapping by oligodendrocytes in response to soluble compounds in an axon-like environment, providing a predictive tool for the discovery of remyelinating therapies.

Alterations of oligodendrocyte progenitor cells (OPCs) with survival time in humans following high impact brain trauma

BackgroundAs there is a lack of comprehensive literature regarding the molecular environment of the human brain emphasizing on oligodendrocyte progenitor cells (OPCs) following high impact brain trauma. The protagonist of OPCs post severe traumatic brain injury (sTBI) provides a significant thrust towards estimating time elapsed since trauma as well as developing novel therapeutic approaches. The present study was carried out to study post trauma alterations pertaining to myelin sheath and oligodendrocyte response with survival time. Materials and methodsIn the present study, victims (both male and female) of sTBI (n = 64) were recruited and contrasted with age and gender matched controls (n = 12). Post mortem brain samples from corpus callosum and grey white matter interface were collected during autopsy examination. Extent of myelin degradation and response of OPC markers Olig-2 and PDGFR-α were evaluated using immunohistochemistry and qRT-PCR. STATA 14.0 statistical software was used for data analysis with P-value<0.05 considered statistically significant. ResultsTimewise qualitative correlation with extent of demyelination performed using LFB-PAS/IHC-MBP, IHC Olig-2 and mRNA expression revealed tendency towards remyelination in both corpus callosum and grey white matter interface. Number of Olig-2 positive cells was significantly higher in sTBI group as compared to control group (P-value: 0.0001). Moreover, mRNA expression studies of Olig-2 showed significant upregulation in sTBI patients. mRNA expression of Olig-2 and PDGFR-α in sTBI patients showed significant variation with respect to survival time (p value:0.0001). ConclusionDetailed assessment of post TBI changes implementing various immunohistochemical and molecular techniques shall potentially reveal intriguing and important inferences in medicolegal practices and neurotherapeutics.

Amburana cearensis seed extract stimulates astrocyte glutamate homeostatic mechanisms in hippocampal brain slices and protects oligodendrocytes against ischemia

BackgroundStroke is a leading cause of death and disability worldwide. A major factor in brain damage following ischemia is excitotoxicity caused by elevated levels of the neurotransmitter glutamate. In the brain, glutamate homeostasis is a primary function of astrocytes. Amburana cearensis has long been used in folk medicine and seed extract obtained with dichloromethane (EDAC) have previously been shown to exhibit cytoprotective activity in vitro. The aim of the present study was to analyse the activity of EDAC in hippocampal brain slices.MethodsWe prepared a dichloromethane extract (EDAC) from A. cearensis seeds and characterized the chemical constituents by 1H and 13C-NMR. Hippocampal slices from P6-8 or P90 Wistar rats were used for cell viability assay or glutamate uptake test. Hippocampal slices from P10-12 transgenic mice SOX10-EGFP and GFAP-EGFP and immunofluorescence for GS, GLAST and GLT1 were used to study oligodendrocytes and astrocytes.ResultsAstrocytes play a critical role in glutamate homeostasis and we provide immunohistochemical evidence that in excitotoxicity EDAC increased expression of glutamate transporters and glutamine synthetase, which is essential for detoxifying glutamate. Next, we directly examined astrocytes using transgenic mice in which glial fibrillary acidic protein (GFAP) drives expression of enhanced green fluorescence protein (EGFP) and show that glutamate excitotoxicity caused a decrease in GFAP-EGFP and that EDAC protected against this loss. This was examined further in the oxygen–glucose deprivation (OGD) model of ischemia, where EDAC caused an increase in astrocytic process branching, resulting in an increase in GFAP-EGFP. Using SOX10-EGFP reporter mice, we show that the acute response of oligodendrocytes to OGD in hippocampal slices is a marked loss of their processes and EDAC protected oligodendrocytes against this damage.ConclusionThis study provides evidence that EDAC is cytoprotective against ischemia and glutamate excitotoxicity by modulating astrocyte responses and stimulating their glutamate homeostatic mechanisms.

Oxygen treatment reduces neurological deficits and demyelination in two animal models of multiple sclerosis.

The objective of the study is to explore the importance of tissue hypoxia in causing neurological deficits and demyelination in the inflamed CNS, and the value of inspiratory oxygen treatment, using both active and passive experimental autoimmune encephalomyelitis (EAE). Normobaric oxygen treatment was administered to Dark Agouti rats with either active or passive EAE, compared with room air-treated, and naïve, controls. Severe neurological deficits in active EAE were significantly improved after just 1 h of breathing approximately 95% oxygen. The improvement was greater and more persistent when oxygen was applied either prophylactically (from immunisation for 23 days), or therapeutically from the onset of neurological deficits for 24, 48, or 72 h. Therapeutic oxygen for 72 h significantly reduced demyelination and the integrated stress response in oligodendrocytes at the peak of disease, and protected from oligodendrocyte loss, without evidence of increased oxidative damage. T-cell infiltration and cytokine expression in the spinal cord remained similar to that in untreated animals. The severe neurological deficit of animals with passive EAE occurred in conjunction with spinal hypoxia and was significantly reduced by oxygen treatment initiated before their onset. Severe neurological deficits in both active and passive EAE can be caused by hypoxia and reduced by oxygen treatment. Oxygen treatment also reduces demyelination in active EAE, despite the autoimmune origin of the disease.

Single nuclei RNA sequencing investigation of the Purkinje cell and glial changes in the cerebellum of transgenic Spinocerebellar ataxia type 1 mice.

Glial cells constitute half the population of the human brain and are essential for normal brain function. Most, if not all, brain diseases are characterized by reactive gliosis, a process by which glial cells respond and contribute to neuronal pathology. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease characterized by a severe degeneration of cerebellar Purkinje cells (PCs) and cerebellar gliosis. SCA1 is caused by an abnormal expansion of CAG repeats in the gene Ataxin1 (ATXN1). While several studies reported the effects of mutant ATXN1 in Purkinje cells, it remains unclear how cerebellar glia respond to dysfunctional Purkinje cells in SCA1. To address this question, we performed single nuclei RNA sequencing (snRNA seq) on cerebella of early stage Pcp2-ATXN1[82Q] mice, a transgenic SCA1 mouse model expressing mutant ATXN1 only in Purkinje cells. We found no changes in neuronal and glial proportions in the SCA1 cerebellum at this early disease stage compared to wild-type controls. Importantly, we observed profound non-cell autonomous and potentially neuroprotective reactive gene and pathway alterations in Bergmann glia, velate astrocytes, and oligodendrocytes in response to Purkinje cell dysfunction.

Disease-associated Oligodendrocyte Responses Across Neurodegenerative Diseases

Disease-associated Oligodendrocyte Responses Across Neurodegenerative Diseases

Disease-associated oligodendrocyte responses across neurodegenerative diseases.

Oligodendrocyte dysfunction has been implicated in the pathogenesis of neurodegenerative diseases, so understanding oligodendrocyte activation states would shed light on disease processes. We identify three distinct activation states of oligodendrocytes from single-cell RNA sequencing (RNA-seq) of mouse models of Alzheimer's disease (AD) and multiple sclerosis (MS): DA1 (disease-associated1, associated with immunogenic genes), DA2 (disease-associated2, associated with genes influencing survival), and IFN (associated with interferon response genes). Spatial analysis of disease-associated oligodendrocytes (DAOs) in the cuprizone model reveals that DA1 and DA2 are established outside of the lesion area during demyelination and that DA1 repopulates the lesion during remyelination. Independent meta-analysis of human single-nucleus RNA-seq datasets reveals that the transcriptional responses of MS oligodendrocytes share features with mouse models. In contrast, the oligodendrocyte activation signature observed in human AD is largely distinct from those observed in mice. This catalog of oligodendrocyte activation states (http://research-pub.gene.com/OligoLandscape/) will be important to understand disease progression and develop therapeutic interventions.

Organotypic whole hemisphere brain slice models to study the effects of donor age and oxygen-glucose-deprivation on the extracellular properties of cortical and striatal tissue

BackgroundThe brain extracellular environment is involved in many critical processes associated with neurodevelopment, neural function, and repair following injury. Organization of the extracellular matrix and properties of the extracellular space vary throughout development and across different brain regions, motivating the need for platforms that provide access to multiple brain regions at different stages of development. We demonstrate the utility of organotypic whole hemisphere brain slices as a platform to probe regional and developmental changes in the brain extracellular environment. We also leverage whole hemisphere brain slices to characterize the impact of cerebral ischemia on different regions of brain tissue.ResultsWhole hemisphere brain slices taken from postnatal (P) day 10 and P17 rats retained viable, metabolically active cells through 14 days in vitro (DIV). Oxygen-glucose-deprivation (OGD), used to model a cerebral ischemic event in vivo, resulted in reduced slice metabolic activity and elevated cell death, regardless of slice age. Slices from P10 and P17 brains showed an oligodendrocyte and microglia-driven proliferative response after OGD exposure, higher than the proliferative response seen in DIV-matched normal control slices. Multiple particle tracking in oxygen-glucose-deprived brain slices revealed that oxygen-glucose-deprivation impacts the extracellular environment of brain tissue differently depending on brain age and brain region. In most instances, the extracellular space was most difficult to navigate immediately following insult, then gradually provided less hindrance to extracellular nanoparticle diffusion as time progressed. However, changes in diffusion were not universal across all brain regions and ages.ConclusionsWe demonstrate whole hemisphere brain slices from P10 and P17 rats can be cultured up to two weeks in vitro. These brain slices provide a viable platform for studying both normal physiological processes and injury associated mechanisms with control over brain age and region. Ex vivo OGD impacted cortical and striatal brain tissue differently, aligning with preexisting data generated in in vivo models. These data motivate the need to account for both brain region and age when investigating mechanisms of injury and designing potential therapies for cerebral ischemia.

Astrocyte and Oligodendrocyte Responses From the Subventricular Zone After Injury.

Under normal conditions, neural stem cells (NSCs or B cells) in the adult subventricular zone (SVZ) give rise to amplifying neural progenitor cells (NPCs or C cells), which can produce neuroblasts (or A cells) that migrate to the olfactory bulb and differentiate into new neurons. However, following brain injury, these cells migrate toward the injury site where they differentiate into astrocytes and oligodendrocytes. In this review, we will focus on recent findings that chronicle how astrocytes and oligodendrocytes derived from SVZ-NSCs respond to different types of injury. We will also discuss molecular regulators of SVZ-NSC proliferation and their differentiation into astrocytes and oligodendrocytes. Overall, the goal of this review is to highlight how SVZ-NSCs respond to injury and to summarize the regulatory mechanisms that oversee their glial response. These molecular and cellular processes will provide critical insights needed to develop strategies to promote brain repair following injury using SVZ-NSCs.