A review: oligodendrocytes in neuronal axonal conduction and methods for enhancing their performance.

OBJECTIVES: This review explores the vital role of oligodendrocytes in axon myelination and efficient neuronal transmission and the impact of dysfunction resulting from neurotransmitter deficiencies related disorders. Furthermore, the review also provides insight into the potential of bionanotechnology for addressing neurodegenerative diseases by targeting oligodendrocytes. METHODS: A review of literature in the field was conducted using Google scholar. Systematic searches were performed to identify relevant studies and reviews addressing the role of oligodendrocytes in neural function, the influence of neurotransmitters on oligodendrocyte differentiation, and the potential of nanotechnology-based strategies for targeted therapy of oligodendrocytes. RESULTS: This review indicates the mechanisms underlying oligodendrocyte differentiation and the influence of neurotransmitters on this process. The importance of action potentials and neurotransmission in neural function and the susceptibility of damaged nerve axons to ischemic or toxic damage is provided in detail. The potential of bionanotechnology for targeting neurodegenerative diseases using nanotechnology-based strategies, including polymeric, lipid-based, inorganic, organic, and biomimetic nanoparticles, suggests better management of neurodegenerative disorders. CONCLUSION: While nanotechnology-based biomaterials show promise for targeted oligodendrocyte therapy in addressing neurodegenerative disorders linked to oligodendrocyte dysfunction, encapsulating neuroprotective agents within nanoparticles offers additional advantages. Nano-based delivery systems effectively protect drugs from degradation and prolong their therapeutic effects, holding promise in overcoming the blood-brain barrier by facilitating drug transport. However, a multifaceted approach is essential to enhance oligodendrocyte differentiation, promote myelin repair, and facilitate myelin dynamics with reduced toxicity. Further research is needed to elucidate the optimal therapeutic approaches and enhance patient outcomes.

DLK signaling in axotomized neurons triggers complement activation and loss of upstream synapses.

Axotomized spinal motoneurons (MNs) lose presynaptic inputs following peripheral nerve injury; however, the cellular mechanisms that lead to this form of synapse loss are currently unknown. Here, we delineate a critical role for neuronal kinase dual leucine zipper kinase (DLK)/MAP3K12, which becomes activated in axotomized neurons. Studies with conditional knockout mice indicate that DLK signaling activation in injured MNs triggers the induction of phagocytic microglia and synapse loss. Aspects of the DLK-regulated response include expression of C1q first from the axotomized MN and then later in surrounding microglia, which subsequently phagocytose presynaptic components of upstream synapses. Pharmacological ablation of microglia inhibits the loss of cholinergic C boutons from axotomized MNs. Together, the observations implicate a neuronal mechanism, governed by the DLK, in the induction of inflammation and the removal of synapses.

Advances of pathogenesis and drug development in amyotrophic lateral sclerosis / 中国药理学通报

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons. ALS patients develop progressive muscle atrophy, muscle weak and paralysis, finally died of respiratory failure. ALS is characterized by fast aggression and high mortality. What' s more, the disease is highly heterogeneous with unclear pathogenesis and lacks effective drugs for therapy. In this review, we summarize the main pathological mechanisms and the current drugs under development for ALS, which may provide a reference for the drug discovery in the future.

Neuronal tau pathology worsens late-phase white matter degeneration after traumatic brain injury in transgenic mice.

Traumatic brain injury (TBI) causes diffuse axonal injury which can produce chronic white matter pathology and subsequent post-traumatic neurodegeneration with poor patient outcomes. Tau modulates axon cytoskeletal functions and undergoes phosphorylation and mis-localization in neurodegenerative disorders. The effects of tau pathology on neurodegeneration after TBI are unclear. We used mice with neuronal expression of human mutant tau to examine effects of pathological tau on white matter pathology after TBI. Adult male and female hTau.P301S (Tg2541) transgenic and wild-type (Wt) mice received either moderate single TBI (s-TBI) or repetitive mild TBI (r-mTBI; once daily × 5), or sham procedures. Acutely, s-TBI produced more extensive axon damage in the corpus callosum (CC) as compared to r-mTBI. After s-TBI, significant CC thinning was present at 6 weeks and 4 months post-injury in Wt and transgenic mice, with homozygous tau expression producing additional pathology of late demyelination. In contrast, r-mTBI did not produce significant CC thinning except at the chronic time point of 4 months in homozygous mice, which exhibited significant CC atrophy (- 29.7%) with increased microgliosis. Serum neurofilament light quantification detected traumatic axonal injury at 1 day post-TBI in Wt and homozygous mice. At 4 months, high tau and neurofilament in homozygous mice implicated tau in chronic axon pathology. These findings did not have sex differences detected. Conclusions: Neuronal tau pathology differentially exacerbated CC pathology based on injury severity and chronicity. Ongoing CC atrophy from s-TBI became accompanied by late demyelination. Pathological tau significantly worsened CC atrophy during the chronic phase after r-mTBI.

Increased IP3R-3 degradation induced by acrylamide promoted Ca2+-dependent calpain activation and axon damage in rats.

Occupational and environmental exposure to acrylamide (ACR) can cause selective peripheral and central nerve fiber degeneration. IP3R-3 is an important transmembrane Ca2+ channel on the endoplasmic reticulum (ER), previous studies have found that ACR could induce Ca2+-dependent calpain activation and axon injury, but the exact role of IP3R-3 in ACR neuropathy is still unclear. Here we show that ACR exposure (40 mg/kg) markedly increased the ubiquitination of IP3R-3 in rat spinal cords, and promoted the degradation of IP3R-3 through the ubiquitin-proteasome pathway. Furthermore, the normal structure of ER, especially the mitochondrial associated membranes (MAMs) component, was significantly impaired in ACR neuropathy, and the ER stress pathway was activated, which indicated that the aberrant increase of cytoplasmic Ca2+ could be attributed the destruction of IP3R-3. Further investigation demonstrated that the proteasome inhibitor MG-132 effectively rescued the IP3R-3 loss, attenuated the intracellular Ca2+ increase, and reduced the axon loss of Neuron 2a (N2a) cells following ACR exposure. Moreover, the calpain inhibitor ALLN also reduced the loss of IP3R-3 and axon injury in N2a cells, but did not alleviate the Ca2+ increase in cytosol, supporting that the abnormal ubiquitination of IP3R-3 was the upstream of the cellular Ca2+ rise and axon damage in ACR neuropathy. Taken together, our results suggested that the aberrant IP3R-3 degradation played an important role in the disturbance of Ca2+ homeostasis and the downstream axon loss in ACR neuropathy, thus providing a potential therapeutic target for ACR neurotoxicity.

Elabela, a Novel Peptide, Exerts Neuroprotective Effects Against Ischemic Stroke Through the APJ/miR-124-3p/CTDSP1/AKT Pathway.

Elabela (ELA), which is the second endogenous peptide ligand of the apelin receptor (APJ) to be discovered, has been widely studied for potential use as a therapeutic peptide. However, its role in ischemic stroke (IS), which is a leading cause of disability and death worldwide and has limited therapeutic options, is uncertain. The aim of the present study was to investigate the beneficial effects of ELA on neuron survival after ischemia and the underlying molecular mechanisms. Primary cortical neurons were isolated from the cerebral cortex of pregnant C57BL/6J mice. Flow cytometry and immunofluorescence showed that ELA inhibited oxygen-glucose deprivation (OGD) -induced apoptosis and axonal damage in vitro. Additionally, analysis of the Gene Expression Omnibus database revealed that the expression of microRNA-124-3p (miR-124-3p) was decreased in blood samples from patients with IS, while the expression of C-terminal domain small phosphatase 1 (CTDSP1) was increased. These results indicated that miR-124-3p and CTDSP1 were related to ischemic stroke, and there might be a negative regulatory relationship between them. Then, we found that ELA significantly elevated miR-124-3p expression, suppressed CTDSP1 expression, and increased p-AKT expression by binding to the APJ receptor under OGD in vitro. A dual-luciferase reporter assay confirmed that CTDSP1 was a direct target of miR-124-3p. Furthermore, adenovirus-mediated overexpression of CTDSP1 exacerbated neuronal apoptosis and axonal damage and suppressed AKT phosphorylation, while treatment with ELA or miR-124-3p mimics reversed these effects. In conclusion, these results indicated that ELA could alleviate neuronal apoptosis and axonal damage by upregulating miR-124-3p and activating the CTDSP1/AKT signaling pathway. This study, for the first time, verified the protective effect of ELA against neuronal injury after ischemia and revealed the underlying mechanisms. We demonstrated the potential for the use of ELA as a therapeutic agent in the treatment of ischemic stroke.

Damaged DNA Is an Early Event of Neurodegeneration in Induced Pluripotent Stem Cell-Derived Motoneurons with UBQLN2P497H Mutation.

Ubiquilin-2 (UBQLN2) mutations lead to familial amyotrophic lateral sclerosis (FALS)/and frontotemporal dementia (FTLD) through unknown mechanisms. The combination of iPSC technology and CRISPR-mediated genome editing technology can generate an iPSC-derived motor neuron (iPSC-MN) model with disease-relevant mutations, which results in increased opportunities for disease mechanism research and drug screening. In this study, we introduced a UBQLN2-P497H mutation into a healthy control iPSC line using CRISPR/Cas9, and differentiated into MNs to study the pathology of UBQLN2-related ALS. Our in vitro MN model faithfully recapitulated specific aspects of the disease, including MN apoptosis. Under sodium arsenite (SA) treatment, we found differences in the number and the size of UBQLN2+ inclusions in UBQLN2P497H MNs and wild-type (WT) MNs. We also observed cytoplasmic TAR DNA-binding protein (TARDBP, also known as TDP-43) aggregates in UBQLN2P497H MNs, but not in WT MNs, as well as the recruitment of TDP-43 into stress granules (SGs) upon SA treatment. We noted that UBQLN2-P497H mutation induced MNs DNA damage, which is an early event in UBQLN2-ALS. Additionally, DNA damage led to an increase in compensation for FUS, whereas UBQLN2-P497H mutation impaired this function. Therefore, FUS may be involved in DNA damage repair signaling.

Physical exercise mitigates neuropathic changes in an animal model for Charcot-Marie-Tooth disease 1X.

Inherited neuropathies of the Charcot-Marie-Tooth (CMT) type 1 are still untreatable diseases of the peripheral nervous system. We have previously shown that macrophages substantially amplify neuropathic changes in various mouse models of CMT1 subforms and that targeting innate immune cells substantially ameliorates disease outcome. However, up to date, specific approaches targeting macrophages pharmacologically might entail side effects. Here, we investigate whether physical exercise dampens peripheral nerve inflammation in a model for an X-linked dominant form of CMT1 (CMT1X) and whether this improves neuropathological and clinical outcome subsequently. We found a moderate, but significant decline in the number of macrophages and an altered macrophage activation upon voluntary wheel running. These observations were accompanied by an improved clinical outcome and axonal preservation. Most interestingly, exercise restriction by ~40% accelerated amelioration of clinical outcome and further improved nerve structure by increasing myelin thickness compared to the unrestricted running group. This myelin-preserving effect of limited exercise was accompanied by an elevated expression of brain-derived neurotrophic factor (BDNF) in peripheral nerves, while the expression of other trophic factors like neuregulin-1, glial cell line-derived neurotrophic factor (GDNF) or insulin-like growth factor 1 (IGF-1) were not influenced by any mode of exercise. We demonstrate for the first time that exercise dampens inflammation and improves nerve structure in a mouse model for CMT1, likely leading to improved clinical outcome. Reducing the amount of exercise does not automatically decrease treatment efficacy, reflecting the need of optimally designed exercise studies to achieve safe and effective treatment options for CMT1 patients.

Repetitive Blast Exposure Produces White Matter Axon Damage without Subsequent Myelin Remodeling: In Vivo Analysis of Brain Injury Using Fluorescent Reporter Mice.

The potential effects of blast exposure on the brain health of military personnel have raised concerns and led to increased surveillance of blast exposures. Neuroimaging studies have reported white matter abnormalities in brains of service members with a history of blast exposure. However, blast effects on white matter microstructure remain poorly understood. As a novel approach to screen for white matter effects, transgenic mice that express fluorescent reporters to sensitively detect axon damage and myelin remodeling were exposed to simulated repetitive blasts (once/day on 5 consecutive days). Axons were visualized using Thy1-YFP-16 reporter mice that express yellow fluorescent protein (YFP) in a broad spectrum of neurons. Swelling along damaged axons forms varicosities that fill with YFP. The frequency and size of axonal varicosities were significantly increased in the corpus callosum (CC) and cingulum at 3 days after the final blast exposure, versus in sham procedures. CC immunolabeling for reactive astrocyte and microglial markers was also significantly increased. NG2CreER;mTmG mice were given tamoxifen (TMX) on days 2 and 3 after the final blast to induce fluorescent labeling of newly synthesized myelin membranes, indicating plasticity and/or repair. Myelin synthesis was not altered in the CC over the intervening 4 or 8 weeks after repetitive blast exposure. These experiments show the advantages of transgenic reporter mice for analysis of white matter injury that detects subtle, diffuse axon damage and the dynamic nature of myelin sheaths. These results show that repetitive low-level blast exposures produce infrequent but significant axon damage along with neuroinflammation in white matter.

Imaging the execution phase of neuroinflammatory disease models.

In vivo imaging of the rodent spinal cord has advanced our understanding of how resident cells of the central nervous system (CNS) respond to neuroinflammation. By combining two-photon imaging and experimental autoimmune encephalomyelitis (EAE), the most widely used rodent model of multiple sclerosis (MS), it has been possible, for example, to study how axons degenerate when confronted with inflammatory cells, how oligodendrocytes get damaged in inflammatory lesions, and how immune cells themselves adapt their phenotype and functionality to the changing lesion environment. Similar approaches are now increasingly used to study other forms of neuroinflammation, such as antibody/complement-mediated neuromyelitis optica spectrum disease (NMOSD). To tackle the most pressing open questions in the field, new biosensors and indicator mice that report the metabolic state and interaction of cells in neuroinflammatory lesions are being developed. Moreover, the field is moving towards new anatomical sites of inflammation, such as the cortical gray matter, but also towards longer observation intervals to reveal the chronic perturbations and adaptations that characterize advanced stages of MS.

Functional Effects of Cuprizone-Induced Demyelination in the Presence of the mTOR-Inhibitor Rapamycin.

Persistent demyelination has been implicated in axon damage and functional deficits underlying neurodegenerative diseases such as multiple sclerosis. The cuprizone diet model of demyelination allows for the investigation of mechanisms underlying timed and reproducible demyelination and remyelination. However, spontaneous oligodendrocyte (OL) progenitor (OPC) proliferation, OPC differentiation, and axon remyelination during cuprizone diet may convolute the understanding of remyelinating events. The Akt (a serine/threonine kinase)/mTOR (the mammalian target of rapamycin) signaling pathway in OLs regulates intermediate steps during myelination. Thus, in an effort to inhibit spontaneous remyelination, the mTOR inhibitor rapamycin has been administered during cuprizone diet. Intrigued by the potential for rapamycin to optimize the cuprizone model by producing more complete demyelination, we sought to characterize the effects of rapamycin on axonal function and myelination. Functional remyelination was assessed by callosal compound action potential (CAP) recordings along with immunohistochemistry in mice treated with rapamycin during cuprizone diet. Rapamycin groups exhibited similar myelination, but significantly increased axonal damage and inflammation compared to non-rapamycin groups. There was minimal change in CAP amplitude between groups, however, a significant decrease in conduction velocity of the slower, non-myelinated CAP component was observed in the rapamycin group relative to the non-rapamycin group. During remyelination, rapamycin groups showed a significant decrease in OPC proliferation and mature OLs, suggesting a delay in OPC differentiation kinetics. In conclusion, we question the use of rapamycin to produce consistent demyelination as rapamycin increased inflammation and axonal damage, without affecting myelination.

Experimental Traumatic Brain Injury Identifies Distinct Early and Late Phase Axonal Conduction Deficits of White Matter Pathophysiology, and Reveals Intervening Recovery.

Traumatic brain injury (TBI) patients often exhibit slowed information processing speed that can underlie diverse symptoms. Processing speed depends on neural circuit function at synapses, in the soma, and along axons. Long axons in white matter (WM) tracts are particularly vulnerable to TBI. We hypothesized that disrupted axon-myelin interactions that slow or block action potential conduction in WM tracts may contribute to slowed processing speed after TBI. Concussive TBI in male/female mice was used to produce traumatic axonal injury in the corpus callosum (CC), similar to WM pathology in human TBI cases. Compound action potential velocity was slowed along myelinated axons at 3 d after TBI with partial recovery by 2 weeks, suggesting early demyelination followed by remyelination. Ultrastructurally, dispersed demyelinated axons and disorganized myelin attachment to axons at paranodes were apparent within CC regions exhibiting traumatic axonal injury. Action potential conduction is exquisitely sensitive to paranode abnormalities. Molecular identification of paranodes and nodes of Ranvier detected asymmetrical paranode pairs and abnormal heminodes after TBI. Fluorescent labeling of oligodendrocyte progenitors in NG2CreER;mTmG mice showed increased synthesis of new membranes extended along axons to paranodes, indicating remyelination after TBI. At later times after TBI, an overall loss of conducting axons was observed at 6 weeks followed by CC atrophy at 8 weeks. These studies identify a progression of both myelinated axon conduction deficits and axon-myelin pathology in the CC, implicating WM injury in impaired information processing at early and late phases after TBI. Furthermore, the intervening recovery reveals a potential therapeutic window.SIGNIFICANCE STATEMENT Traumatic brain injury (TBI) is a major global health concern. Across the spectrum of TBI severities, impaired information processing can contribute to diverse functional deficits that underlie persistent symptoms. We used experimental TBI to exploit technical advantages in mice while modeling traumatic axonal injury in white matter tracts, which is a key pathological feature of human TBI. A combination of approaches revealed slowed and failed signal conduction along with damage to the structure and molecular composition of myelinated axons in the white matter after TBI. An early regenerative response was not sustained yet reveals a potential time window for intervention. These insights into white matter abnormalities underlying axon conduction deficits can inform strategies to improve treatment options for TBI patients.

Chronic demyelination-induced seizures.

Multiple sclerosis (MS) patients are three to six times more likely to develop epilepsy compared to the rest of the population. Seizures are more common in patients with early onset or progressive forms of the disease and prognosticate rapid progression to disability and death. Gray matter atrophy, hippocampal lesions, interneuron loss, and elevated juxtacortical lesion burden have been identified in MS patients with seizures; however, translational studies aimed at elucidating the pathophysiological processes underlying MS epileptogenesis are limited. Here, we report that cuprizone-mediated chronically demyelinated (9-12weeks) mice exhibit marked changes to dorsal hippocampal electroencephalography (EEG) and evidence of overt seizure activity. Immunohistochemical (IHC) analyses within the hippocampal CA1 region revealed extensive demyelination, loss of parvalbumin (PV+) interneurons, widespread gliosis, and changes in aquaporin-4 (AQP4) expression. Our results suggest that chronically demyelinated mice are a valuable model with which we may begin to understand the mechanisms underlying demyelination-induced seizures.

Myelin basic protein associates with AßPP, Aß1-42, and amyloid plaques in cortex of Alzheimer's disease brain.

The goal of this study was to show that myelin and axons in cortical gray matter are damaged in Alzheimer's disease (AD) brain. Superior temporal gyrus gray matter of AD patients (9 male, 14 female) was compared to cognitively normal controls (8 male, 7 female). Myelin basic protein (MBP) and a degraded myelin basic protein complex (dMBP) were quantified by Western blot. Brain sections were immunostained for MBP, dMBP, axonal neurofilament protein (NF), autophagy marker microtubule-associated proteins 1A/B light chain 3B precursor (LC3B), amyloid-ß protein precursor (AßPP), and amyloid markers amyloid ß1-42 (Aß1-42) and FSB. Co-immunoprecipitation and mass spectroscopy evaluated interaction of AßPP/Aß1-42 with MBP/dMBP. Evidence of axonal injury in AD cortex included appearance of AßPP in NF stained axons, and NF at margins of amyloid plaques. Evidence of myelin injury in AD cortex included (1) increased dMBP in AD gray matter compared to control (p < 0.001); (2) dMBP in AD neurons; and (3) increased LC3B that co-localized with MBP. Evidence of interaction of AßPP/Aß1-42 with myelin or axonal components included (1) greater binding of dMBP with AßPP in AD brain; (2) MBP at the margins of amyloid plaques; (3) dMBP co-localized with Aß1-42 in the core of amyloid plaques in AD brains; and (4) interactions between Aß1-42 and MBP/dMBP by co-immunoprecipitation and mass spectrometry. We conclude that damaged axons may be a source of AßPP. dMBP, MBP, and NF associate with amyloid plaques and dMBP associates with AßPP and Aß1-42. These molecules could be involved in formation of amyloid plaques.

Bilateral common carotid artery occlusion induced brain lesions in rats: A longitudinal diffusion tensor imaging study.

Bilateral common carotid artery occlusion (BCCAO) has been widely used to reproduce the white matter (WM) and gray matter (GM) damage associated with chronic cerebral hypoperfusion (CCH). This study investigated whether diffusion tensor imaging (DTI) could be used at the early stages of disease to assess brain damage induced by BCCAO. To this end, DTI, together with histological methods, was used to evaluate the progression of WM lesions and GM neurodegeneration following BCCAO. The DTI was sufficiently sensitive to detect WM abnormalities in selected regions of the brain at 4weeks after BCCAO. These abnormalities may indicate damage to the myelin and axons in the optic nerve (ON) and optic tract (OT). Our longitudinal results showed that DTI could be used to detect abnormalities of the WM and GM in select regions of the brain as early as 2days after ligation. The DTI parameter patterns of change were region-specific throughout the detection time course. Lesions of the external capsule (EC) and periventricular hypothalamic nucleus (Pe) have not been thoroughly studied before. We found that the EC and Pe were both vulnerable to BCCAO and that the associated lesions could be detected using DTI. The current study demonstrated that in vivo DTI could potentially be used to measure WM damage evolution in a BCCAO rat model as well as early brain injury following CCH.

Advance in the Research of Axonal Damage Mechanism in Multiple Sclerosis (review) / 中国康复理论与实践

@#To review the advance in research of axonal damage mechanism of multiple sclerosis (MS) in recent years. To explain the evidence and effect of morphology and imageology in axonal damage of MS. And, to show the progression in the mechanism of axonal damage in MS.