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BACKGROUND: A bioactive myelin basic protein (MBP) fragment, comprising MBP84-104, is released in sciatic nerve after chronic constriction injury (CCI). Intraneural injection (IN) of MBP84-104 in an intact sciatic nerve is sufficient to induce persistent neuropathic pain-like behavior via robust transcriptional remodeling at the injection site and ipsilateral dorsal root ganglia (DRG) and spinal cord. The sex (female)-specific pronociceptive activity of MBP84-104 associates with sex-specific changes in cholesterol metabolism and activation of estrogen receptor (ESR)1 signaling. METHODS: In male and female normal and post-CCI rat sciatic nerves, we assessed: (i) cholesterol precursor and metabolite levels by lipidomics; (ii) MBP84-104 interactors by mass spectrometry of MBP84-104 pull-down; and (iii) liver X receptor (LXR)α protein expression by immunoblotting. To test the effect of LXRα stimulation on IN MBP84-104-induced mechanical hypersensitivity, the LXRα expression was confirmed along the segmental neuraxis, in DRG and spinal cord, followed by von Frey testing of the effect of intrathecally administered synthetic LXR agonist, GW3965. In cultured male and female rat DRGs exposed to MBP84-104 and/or estrogen treatments, transcriptional effect of LXR stimulation by GW3965 was assessed on downstream cholesterol transporter Abc, interleukin (IL)-6, and pronociceptive Cacna2d1 gene expression. RESULTS: CCI regulated LXRα ligand and receptor levels in nerves of both sexes, with cholesterol precursors, desmosterol and 7-DHC, and oxysterol elevated in females relative to males. MBP84-104 interacted with nuclear receptor coactivator (Ncoa)1, known to activate LXRα, injury-specific in nerves of both sexes. LXR stimulation suppressed ESR1-induced IL-6 and Cacna2d1 expression in cultured DRGs of both sexes and attenuated MBP84-104-induced pain in females. CONCLUSION: The injury-released bioactive MBP fragments induce pronociceptive changes by selective inactivation of nuclear transcription factors, including LXRα. By Ncoa1 sequestration, bioactive MBP fragments render LXRα function to counteract pronociceptive activity of estrogen/ESR1 in sensory neurons. This effect of MBP fragments is prevalent in females due to high circulating estrogen levels in females relative to males. Restoring LXR activity presents a promising therapeutic strategy in management of neuropathic pain induced by bioactive MBP.

Brain ischemia, a condition in which the brain is deprived of blood flow, can lead to a stroke due to blocked or unstable blood vessels. Global cerebral ischemia (GCI), characterized by an interruption in blood flow, deprives the brain of oxygen and nutrients, producing reactive oxygen species (ROS) that trigger cell death, which kills nerve cells. Microplastics (MPs), tiny environmental pollutants, can enter the human body through contaminated food, water, disposable items, cosmetics, and more. Once in the brain, MPs can increase neuroinflammation by overstimulating inflammatory factors such as microglia. MPs can also damage neurons by scratching myelin and microtubules, slowing signal transduction, causing cognitive impairment, and leading to neuronal death. Furthermore, microtubule damage may result in the release of phosphorylated tau proteins, potentially linked to Alzheimer's disease. We hypothesized that MPs could exacerbate neuroinflammation and microtubule destruction after GCI, leading to increased neuronal death. To test this hypothesis, we administered MPs (0.5 µm) orally at a dose of 50 mg/kg before and after inducing GCI. Staining techniques such as Fluoro-Jade B (FJB), ionized calcium-binding adaptor molecule 1 (Iba-1), cluster of differentiation 68 (CD68), myelin basic protein (MBP), and microtubule-associated protein 2 (MAP2) were used, along with Western blot analysis for interleukin-6 (IL-6), TNF-α, tau-5, and phospho-tau (S396) to evaluate the effects of MPs on neuronal cell death, neuroinflammation, and microtubule destruction. The results showed that MP accumulation significantly increased neuroinflammation, microtubule disruption, and neuronal cell death in the GCI-MP group compared to the GCI-vehicle group. Therefore, this study suggests that MP accumulation in daily life may contribute to the exacerbation of the disease, potentially leading to severe neuronal cell death after GCI. [ABSTRACT FROM AUTHOR]

Diabetes is a multifunctional chronic disease that affects both the central and/or peripheral nervous systems. This study assessed whether nicotinamide (NAm) or conjugate of nicotinic acid with gamma-aminobutyric acid (N-GABA) could be potential neuroprotective agents against type 1 diabetes (T1D)-induced nervous system impairments in rats. After six weeks of T1D, induced by streptozotocin, nonlinear male Wistar rats were treated for two weeks with NAm (100 mg/kg, i. p.) or N-GABA (55 mg/kg, i. p.). Expression levels of myelin basic protein (MBP) were analyzed by immunoblotting. Polyol pathway parameters of the sciatic nerves were assessed spectrophotometrically, and their structure was examined histologically. NAm had no effect on blood glucose or body weight in T1D, while N-GABA reduced glucose by 1.5-fold. N-GABA also increased MBP expression by 1.48-fold, enhancing neuronal myelination, while NAm showed no such effect. Activation of the polyol pathway was observed in the T1D sciatic nerves. Both compounds decreased sorbitol content and aldose reductase activity, thereby alleviating changes similar to primary degeneration in the sciatic nerves and preventing peripheral neuropathy development. These results demonstrate that NAm and, more notably, N-GABA may exert neuroprotective effects against T1D-induced nervous system impairments by increasing MBP expression levels, improving myelination processes in the brain, inhibiting the polyol pathway, and partially restoring morphometric parameters in the sciatic nerves. This suggests their potential therapeutic efficacy as promising agents for the prevention of T1D-induced nervous system alterations. [ABSTRACT FROM AUTHOR]

• Psychological stress induces emotional disorder behaviors and amygdala myelin damage. • Amygdala demyelination mediates psychological stress–induced depressive behaviors. • Psychological stress induces activation of microglia and NLRP3 inflammasome in the amygdala. • P2X7R/NLRP3 cascade activation partially contributes to amygdala myelin damage in response to psychological stress. Psychological stress can lead to emotional disorders, such as anxiety and depression; however, the underlying mechanisms are complicated and remain unclear. In this study, we established a mouse psychological stress model using an improved communication box, in which the psychologically stressed mice received visual, auditory, and olfactory emotional stimuli from the mice receiving electric foot shock, thus avoiding physical stress interference. After the 14-day psychological stress paradigm, our mice exhibited a significant increase in depressive and anxious behaviors. We then performed proteomic liquid chromatography–tandem mass spectrometry for proteomic data analysis of the amygdala, and the results demonstrated that differentially expressed proteins were more enriched in myelin-related biological processes, cellular components, and molecular functions, indicating a correlation between psychological stress–induced emotional disorders and amygdala myelin damage. Molecular and morphological evidence further confirmed that psychological stress damages myelin ultrastructure, downregulated myelin basic protein and proteolipid protein expression, and reduced oligodendrocyte proliferation in the amygdala. Moreover, clemastine, an antimuscarinic and antihistaminic compound that has been shown to enhance oligodendrocyte differentiation and myelination, rescued depressive behaviors accompanied by increased oligodendrogenesis. In the amygdala, psychological stress was also noted to activate microglia and increase the levels of NOD-like receptor protein 3 (NLRP3) and the proinflammatory cytokines interleukin 1β and tumor necrosis factor α, as indicated by ELISA and Western blot analyses. Moreover, in stressed mice, the administration of Brilliant Blue G, a purinergic ligand-gated ion channel 7 receptor (P2X7R) antagonist, completely reversed the increases in NLRP3 and cleaved caspase-1 levels and partially prevented amygdala myelin damage. In conclusion, amygdala demyelination may mediate psychological stress–induced emotional disorders, and P2X7R/NLRP3 cascade activation partially contributes to amygdala myelin damage after psychological stress. [ABSTRACT FROM AUTHOR]

Neural stem cells (NSCs) are found along the neuraxis of the developing and mature central nervous system. They are found in defined niches that have been shown to regulate NSC behavior in a regionally distinct manner. Specifically, previous research has shown that myelin basic protein (MBP), when presented in the spinal cord niche, inhibits NSC proliferation and oligodendrogenesis. Herein, we investigate the cell-based mechanism(s) underlying this spinal-cord niche-derived MBP-mediated inhibition. We used reporter mice to sort for subpopulations of cells and found that spinal cord niche-derived microglia release a soluble factor in response to MBP that is responsible for NSC inhibition. Microglia, but not other niche cells, release soluble CD40/TNFRSF5 (sCD40) in the presence of MBP which may indirectly reduce activation of transmembrane CD40/TNFRSF5 receptor on both spinal cord and brain NSCs. This is consistent with sCD40 binding to CD40 ligand (CD40L) thereby preventing CD40 receptor binding on NSCs and inhibiting NSC proliferation. The identification of the cell-based mechanism that regulates NSC behavior in response to MBP, which is dysregulated in injury/disease, provides insight into a potential target for strategies to enhance neural repair through endogenous stem cell activation. [ABSTRACT FROM AUTHOR]

Purpose: To compare the myelin water fraction (MWF) measurements between 3 T and 7 T and between in vivo and ex vivo human brains, and to investigate the relationship between multi‐echo gradient‐echo (mGRE)‐based 3D MWF and myelin content using histological staining, which has not been validated in the human brain. Methods: In this study, we performed 3D mGRE‐based MWF measurements on five ex vivo human brain hemispheres and five healthy volunteers at 3 T and 7 T with 1 mm isotropic resolution. The data were fitted with the T2*$$ {\mathrm{T}}_2^{\ast } $$ based on a three compartment complex‐valued model to estimate MWF. We obtained myelin basic protein (MBP) staining from two tissue blocks and co‐registered the MWF map and histology image for voxel‐wise correlation between the two. Results: The MWF values measured from 7 T were overall higher than 7 T, but data between the two field strength demonstrated high correlations both in vivo (r = 0.88) and ex vivo (r = 0.83) across 19 white matter regions. Moreover, the MWF measurements showed a good agreement between in vivo and ex vivo assessments at 3 T (r = 0.61) and 7 T (r = 0.54). Based on MBP staining, the MWF values exhibited strong positive correlations with myelin content on both 3 T (r = 0.68 and r = 0.78 for the two tissue blocks) and 7 T (r = 0.64 and r = 0.82 for the two tissue blocks). Conclusion: The findings demonstrated that the mGRE‐based MWF mapping can be used to quantify myelin content in the human brain, despite the field‐strength dependency of the measurements. [ABSTRACT FROM AUTHOR]

The ApoE ε4 allele (APOEε4) is a major genetic risk factor for sporadic Alzheimer's disease (AD) and is linked to demyelination and cognitive decline. However, its effects on the lipid transporters apolipoprotein E (ApoE) and fatty acid-binding protein 7 (Fabp7), which are crucial for the maintenance of myelin in white matter (WM) during the progression of AD remain underexplored. To evaluate the effects of APOEε4 on ApoE, Fabp7 and myelin in the WM of the frontal cortex (FC), we examined individuals carrying one ε4 allele that came to autopsy with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and mild to moderate AD compared with non-carrier counterparts. ApoE, Fabp7 and Olig2 immunostaining was used to visualize cells, whereas myelin basic protein (MBP) immunocytochemistry and luxol fast blue (LFB) histochemistry of myelin in the WM of the FC were combined with quantitative morphometry. We observed increased numbers of ApoE-positive astrocytes in the WM of both NCI and MCI APOEε4 carriers compared with non-carriers, whereas Fabp7-positive cells were elevated only in AD. Conversely, Olig2 cell counts and MBP immunostaining decreased in MCI APOEε4 carriers compared to non-carriers, while LFB levels were higher in NCI APOEε4 carriers compared to non-carriers. Although no correlations were found between ApoE, Fabp7, and cognitive status, LFB measurements were positively correlated with perceptual speed, global cognition, and visuospatial scores in APOEε4 carriers across clinical groups. The present findings suggest that the ε4 allele compromises FC myelin homeostasis by disrupting the lipid transporters ApoE, Fabp7 and myelination early in the onset of AD. These data support targeting cellular components related to WM integrity as possible treatments for AD. [ABSTRACT FROM AUTHOR]

[Display omitted] • TNIRL is a non-invasive and effective treatment for cognitive impairment in PND mice. • Demyelination contributes 'to the occurrence of PND and TNIRL promotes remyelination. • TNIRL may be a novel therapeutic approach for PND and other demyelination diseases. Postoperative neurocognitive disorder (PND) is a prevalent complication following surgery and anesthesia, characterized by progressive cognitive decline. The precise etiology of PND remains unknown, and effective targeted therapeutic strategies are lacking. Transcranial near-infrared light (tNIRL) has shown potential benefits for cognitive dysfunction diseases, but its effect on PND remains unclear. Our previous research indicated a close association between demyelination and PND. In other central nervous system (CNS) disorders, tNIRL has been demonstrated to facilitate remyelination in response to demyelination. In this study, we established the PND model in 18-month-old male C57BL/6 mice using isoflurane anesthesia combined with left common carotid artery exposure. Following surgery, PND-aged mice were subjected to daily 2.5-minute tNIRL treatment at 810 nm for three consecutive days. Subsequently, we observed that tNIRL significantly improved cognitive performance and reduced inflammatory cytokine levels in the hippocampus of PND mice. Furthermore, tNIRL increased the expression of oligodendrocyte transcription factor 2 (OLIG2) and myelin basic protein (MBP), promoting remyelination while enhancing synaptic function-associated proteins such as synaptophysin (SYP) and postsynaptic density protein 95 (PSD95). Further investigation revealed that tNIRL may activate the AKT1/mTOR pathway to facilitate remyelination in PND mice. These findings indicate that tNIRL is a novel non-invasive therapeutic approach for treating PND. [ABSTRACT FROM AUTHOR]

Background: Following transection, nerve repair using the polylactic acid (PLA) conduit is an effective option. In addition, inosine treatment has shown potential to promote nerve regeneration. Therefore, this study aimed to investigate the regenerative potential of inosine after nerve transection and polylactic acid conduit repair. Methods: C57/Black6 mice were subjected to sciatic nerve transection, repair with PLA conduit, and intraperitoneal injection of saline or inosine 1 h after injury and daily for 1 week. To assess motor and sensory recovery, functional tests were performed before and weekly up to 8 weeks after injury. Following, to evaluate the promotion of regeneration and myelination, electroneuromyography, morphometric analysis and immunohistochemistry were then performed. Results: Our results showed that the inosine group had a greater number of myelinated nerve fibers (1,293 ± 85.49 vs. 817 ± 89.2), an increase in neurofilament high chain (NFH) and myelin basic protein (MBP) immunolabeling and a greater number of fibers within the ideal g-ratio (453.8 ± 45.24 vs. 336.6 ± 37.01). In addition, the inosine group presented a greater adenosine A2 receptor (A2AR) immunolabeling area. This resulted in greater compound muscle action potential amplitude and nerve conduction velocity, leading to preservation of muscle and neuromuscular junction integrity, and consequently, the recovery of motor and sensory function. Conclusion: Our findings suggest that inosine may enhance regeneration and improve both motor and sensory function recovery after nerve transection when repaired with a poly-lactic acid conduit. This advances the understanding of biomaterials and molecular treatments. [ABSTRACT FROM AUTHOR]

Deletion and duplication in the human 16p11.2 chromosomal region are closely linked to neurodevelopmental disorders, specifically autism spectrum disorder. Data from neuroimaging studies suggest white matter microstructure aberrations across these conditions. In 16p11.2 deletion and duplication carriers, potential gene dosage effects may impact white matter organisation, contributing to phenotypes including impaired cognition. However, the biological mechanisms underlying this white matter pathology remain unclear. To bridge this knowledge gap, we utilised mouse models of 16p11.2 deletion and duplication to explore changes in corpus callosum oligodendrocytes, myelination, axon caliber, and astrocytes. Immunofluorescence staining was employed to measure lineage and mature oligodendrocyte numbers, as well as myelin basic protein and glial fibrillary acidic protein fluorescence intensity. Transmission electron microscopy was utilised to evaluate axonal structural alterations related to myelin, such as myelinated axon percentage, diameter, myelin thickness, and g-ratio. Our findings reveal changes in the number of mature oligodendrocytes, myelination levels, axon diameter, and astrocytes in the corpus callosum of mice with 16p11.2 deletion and duplication. Deletion mice displayed a tendency toward reduced counts of mature oligodendrocytes and myelination levels, while duplication mice exhibited a notable increase. Axon diameter variations included a significant increase in axon diameter and myelin thickness in both deletion and duplication mice, but with irregular structure in duplication mice. Variances in astrocytes between genotypes showed significant early increases in development for both deletion and duplication mice compared to wild-type mice, with this rise sustained in duplication mice but significantly diminished in deletion mice at a later stage. Our research reveals changes in the biological mechanisms impacting white matter. Comparison of reciprocal trends in 16p11.2 deletion and duplication mice with wild-type mice suggests the possibility of gene dosage effects. Identification of these mechanisms offers an initial step in unveiling therapeutic targets for associated neurodevelopmental disorder phenotypes. [ABSTRACT FROM AUTHOR]

The study published in Acta Neuropathologica explores white matter pathology in frontotemporal lobar degeneration (FTLD) caused by progranulin gene mutations (FTLD-GRN). The research indicates that FTLD-GRN patients exhibit more severe cerebral white matter changes compared to other FTLD subtypes, with significant myelin loss in the frontal lobe. The study suggests that the white matter pathology in FTLD-GRN may be a primary defect in myelin maintenance, potentially related to reduced progranulin levels and altered microglial activity. These findings could aid in developing disease-specific biomarkers and targeted therapies for FTLD-GRN. [Extracted from the article]

Background: It is well known that myelin disruption and neuroinflammation are early and distinct pathological hallmarks in multiple system atrophy (MSA) as well as in idiopathic Parkinson’s disease and in other atypical Parkinsonian syndromes. The objective of this study was to assess the value of non-neuronal biomarker candidates that reflect myelin disruption and neuroinflammation. Methods: Myelin basic protein (MBP) and the soluble form of TREM2 were quantified in a comprehensive movement disorder cohort from two different neurological centers, comprising a total of 171 CSF samples. Commercially available ELISA systems were employed for quantification. Results: The results of the MBP analysis revealed a significant increase in cerebrospinal fluid (CSF) MBP levels in all atypical Parkinsonian conditions compared to PD. This differentiation was more pronounced in the MSA-c subtype compared to MSA-p. Receiver operating characteristic (ROC) analysis revealed a significant discrimination between PD and MSA (p = 0.032, AUC = 0.70), PD and DLB (p = 0.006, AUC = 0.79) and PD and tauopathies (p = 0.006, AUC = 0.74). The results of the TREM2 analysis demonstrated no significant differences between the PD and atypical Parkinsonian groups if not adjusted for confounders. After adjusting for age, sex, and disease duration, the PD group exhibited significantly higher TREM2 levels compared to the DLB group (p = 0.002). Conclusions: In conclusion, MBP, but not TREM2, is elevated in the CSF of not only MSA but in all atypical Parkinsonian conditions compared to idiopathic Parkinson’s disease. This highlights the value of the evaluation of myelin/oligodendrocyte-associated markers in neurodegenerative movement disorders. [ABSTRACT FROM AUTHOR]

BACKGROUND: Neurotrophins represent a novel therapeutic approach for spinal cord injury, showing promising clinical applicability. Autophagy modulation is one of the mechanisms by which neurotrophins exert their effects, yet the specific signaling pathways involved remain unclear. OBJECTIVE: To explore how neurotrophin-3 (NT-3) modulates autophagy in oligodendrocytes via switching between P75NTR and TrkC receptors and promotes neurological function recovery after spinal cord injury, aiming to further clarify the specific molecular mechanisms involved. METHODS: Twenty-four Sprague-Dawley rats were randomly divided into three groups: sham operation, spinal cord injury, and NT-3 groups. The therapeutic effect of NT-3 on spinal cord injury in rats was evaluated using the Basso, Beattie, and Bresnahan locomotor rating scale. The expression levels of NT-3, Olig1, myelin basic protein, and the autophagy marker LC3B in rat spinal cord tissue were detected by western blot. In a cellular experiment, oligodendrocytes were cultured in vitro and divided into six groups: oxygen-glucose deprivation (OGD), OGD+NT-3, OGD+NT-3+P75NTR plasmid, OGD+NT-3+TrkC plasmid, OGD+ 3-methyladenine (an autophagy inhibitor), and OGD+rapamycin (an autophagy activator). Oligodendrocyte morphology was observed under a light microscope, cell apoptosis was assessed by TUNEL staining, and the expression of TrkC receptor, P75NTR, LC3B, and the phosphorylation status of the PI3K/AKT/mTOR and AMPK/mTOR signaling pathways were evaluated by western blot. RESULTS AND CONCLUSION: Animal experiments demonstrated that compared with the sham operation group, NT-3 expression significantly increased after spinal cord injury (P < 0.05); exogenous NT-3 treatment accelerated neurological function recovery in rats post spinal cord injury (P < 0.05) and increased the expression of Olig1 and myelin basic proteins (P < 0.05). Cellular experiments revealed that 3 hours marked the early to middle/late phase transition. Compared with the OGD group, oligodendrocytes in the OGD+NT-3 group could maintain their morphology for a longer period of time, TrkC receptor expression was lower in the early phase and significantly upregulated in the middle/late phase (P < 0.05), whereas P75NTR protein expression was upregulated in the early phase and downregulated in the middle/late phase (P < 0.05), and autophagy levels showed an initial increase followed by a decrease (P < 0.05). By comparing the morphology and TUNEL staining results of cells in the OGD+NT-3, OGD+rapamycin, and OGD+3-methyladenine groups, we found that either promoting or inhibiting autophagy alone had adverse effects on oligodendrocyte survival, whereas modulating autophagy in a manner similar to NT-3 could maximally maintain cell survival. NT-3 could promote autophagy in the early phase via the P75NTR/AMPK/mTOR signaling pathway and inhibit autophagy in the later phase through the TrkC/PI3K/AKT/mTOR signaling pathway. Based on these findings, it is concluded that NT-3 can bidirectionally regulate autophagy in oligodendrocytes through the switching of P75NTR/TrkC receptors, thereby maintaining cell survival and facilitating the recovery of neurological functions in rats after spinal cord injury. [ABSTRACT FROM AUTHOR]

Pancreatic encephalopathy (PE) is a frequent complication of acute pancreatitis. This study explored the mechanism of taraxasterol (TAS) in PE treatment by inhibiting pyroptosis via L1 cell adhesion molecule (L1CAM) up-regulation. PE rat models were established and treated with TAS, NLRP3 activator, and sh-L1CAM lentivirus. Serum amylase and lipase activities and Serum, hippocampus, and amygdala IL-18 and IL-1β levels were determined by ELISA, followed by TUNEL and HE staining. Rat nerve injury was evaluated by modified Neurological Severity Score (mNSS). Spontaneous behaviors, learning, memory, and emotions in rats were separately assessed by open field, new object recognition, tail suspension, and forced swimming tests. Microstructures of hippocampal CA1 region and amygdala were observed. NLRP3 + GSDMD + cells, pyroptosis markers, L1CAM, and myelin basic protein (MBP) were detected. PE rat model displayed elevated serum amylase and lipase activities and IL-18 and IL-1β levels, increased mNSS, shortened moving distance, reduced discrimination rate, prolonged immobility time, pathological damage in hippocampal CA1 region and amygdala, increased TUNEL-positive and NLRP3 + GSDMD + cells, raised NLRP3, cleaved caspase-1, GSDMD-N, IL-1β and IL-18 levels, and reduced L1CAM and MBP levels. TAS mitigated behavioral deficits and brain injury and curbed NLRP3-mediated pyroptosis in hippocampal CA1 region and amygdala in PE rats. NLRP3 activation partly averted the beneficial impacts of TAS on PE rats. TAS suppressed nerve cell pyroptosis and facilitated myelin regeneration by up-regulating L1CAM. L1CAM silencing partially abrogated TAS’s effect on behavioral deficits and brain injury in PE rats. TAS treated PE by inhibiting pyroptosis via L1CAM up-regulation. [ABSTRACT FROM AUTHOR]

Abstract Background Angelman syndrome (AS), a severe neurodevelopmental disorder resulting from the loss of the maternal UBE3A gene, is marked by changes in the brain’s white matter (WM). The extent of WM abnormalities seems to correlate with the severity of clinical symptoms, but these deficits are still poorly characterized or understood. This study provides the first large-scale measurement of WM volume reduction in children with AS. Furthermore, we probed the possibility of underlying WM neuropathology by examining the progression of myelination in an AS mouse model. Methods We conducted magnetic resonance imaging (MRI) on children with AS (n = 32) and neurotypical controls (n = 99) aged 0.5–12 years. In parallel, we examined myelination in postnatal Ube3a maternal-null mice (Ube3a m−/p+; AS model), Ube3a paternal-null mice (Ube3a m+/p−), and wildtype controls (Ube3a m+/p+) using MRI, immunohistochemistry, western blotting, and electron microscopy. Results Our data revealed that AS individuals exhibit significant reductions in brain volume by ~ 1 year of age, and by 6–12 years of age WM is reduced by 26% and gray matter by 21%—approximately twice the reductions observed in the adult AS mouse model. Our AS mouse model saw a global delay in the onset of myelination, which normalized within days (likely corresponding to months or years in human development). This myelination delay is caused by the loss of UBE3A in neurons rather than UBE3A haploinsufficiency in oligodendrocytes. Interestingly, ultrastructural analyses did not reveal abnormalities in myelinated or unmyelinated axons. Limitations It is difficult to extrapolate the timing and duration of the myelination delay observed in AS model mice to individuals with AS. Conclusions This study reveals WM deficits as a hallmark in children with AS, demonstrating for the first time that these deficits are already apparent at 1 year of age. Parallel studies in a mouse model of AS show these deficits occur alongside the delayed onset of myelination, which results from the loss of neuronal (but not glial) UBE3A, though the causal relationship between these phenotypes remains to be determined. These findings emphasize the potential of WM as both a therapeutic target for interventions and a valuable biomarker for tracking the progression of AS and the effectiveness of potential treatments.

Multiple sclerosis (MS) is a devastating autoimmune disease that leads to the destruction of the myelin sheath in the human central nervous system (CNS). Infection by viruses and bacteria has been found to be strongly associated with the onset of MS or its severity. We postulated that the immune system's attack on the myelin sheath could be triggered by viruses and bacteria antigens that resemble myelin sheath components. An in-silico bioinformatics approach was undertaken in order to identify viral and bacterial antigens that resemble myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP). To this end, we simultaneously analyzed both protein structures and amino acid sequences from viral and bacterial proteins and compared them to MOG and MBP. Possible associations between MBP and human parvovirus B19 (HPV-B19) and adeno-associated virus 4 (AAV-4) capsid protein structures were identified. MBP and MOG were associated with antigens from different viruses and bacteria, including Aspergillus species, Lactobacillus, Burkholderia, Clostridium, Schizosaccharomyces, SARS-CoV-2, and some gut flora metabolites. We also identified similarities between MBP and MOG proteins and bile salt hydrolase (BSH), glycosyltransferase (WcfQ), and Wzy enzymes. Identical amino acids between MBP and BSH at the active site, and protected amino acids in MOG aligning with WcfQ and Wzy enzymes were observed. Overall, our results offer valuable insights into the role of different viral and bacterial protein antigens in MS pathogenesis and suggest the possibility of identifying new therapeutic targets using in silico bioinformatics approaches. Our proposed approach could also likely be adapted for other CNS diseases in order to develop new biological insights and treatments. [ABSTRACT FROM AUTHOR]

Background: Angelman syndrome (AS), a severe neurodevelopmental disorder resulting from the loss of the maternal UBE3A gene, is marked by changes in the brain's white matter (WM). The extent of WM abnormalities seems to correlate with the severity of clinical symptoms, but these deficits are still poorly characterized or understood. This study provides the first large-scale measurement of WM volume reduction in children with AS. Furthermore, we probed the possibility of underlying WM neuropathology by examining the progression of myelination in an AS mouse model. Methods: We conducted magnetic resonance imaging (MRI) on children with AS (n = 32) and neurotypical controls (n = 99) aged 0.5–12 years. In parallel, we examined myelination in postnatal Ube3a maternal-null mice (Ube3am−/p+; AS model), Ube3a paternal-null mice (Ube3am+/p−), and wildtype controls (Ube3am+/p+) using MRI, immunohistochemistry, western blotting, and electron microscopy. Results: Our data revealed that AS individuals exhibit significant reductions in brain volume by ~ 1 year of age, and by 6–12 years of age WM is reduced by 26% and gray matter by 21%—approximately twice the reductions observed in the adult AS mouse model. Our AS mouse model saw a global delay in the onset of myelination, which normalized within days (likely corresponding to months or years in human development). This myelination delay is caused by the loss of UBE3A in neurons rather than UBE3A haploinsufficiency in oligodendrocytes. Interestingly, ultrastructural analyses did not reveal abnormalities in myelinated or unmyelinated axons. Limitations: It is difficult to extrapolate the timing and duration of the myelination delay observed in AS model mice to individuals with AS. Conclusions: This study reveals WM deficits as a hallmark in children with AS, demonstrating for the first time that these deficits are already apparent at 1 year of age. Parallel studies in a mouse model of AS show these deficits occur alongside the delayed onset of myelination, which results from the loss of neuronal (but not glial) UBE3A, though the causal relationship between these phenotypes remains to be determined. These findings emphasize the potential of WM as both a therapeutic target for interventions and a valuable biomarker for tracking the progression of AS and the effectiveness of potential treatments. [ABSTRACT FROM AUTHOR]

Military breachers are routinely exposed to repetitive low-level blast overpressure, placing them at elevated risk for long-term neurological sequelae. Mounting evidence suggests that circulating brain-reactive autoantibodies, generated following CNS injury, may serve as both biomarkers of cumulative damage and drivers of secondary neuroinflammation. In this study, we compared circulating autoantibody profiles in military breachers (n = 18) with extensive blast exposure against unexposed military controls (n = 19). Using high-sensitivity immunoassays, we quantified IgG and IgM autoantibodies targeting glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and pituitary (PIT) antigens. Breachers exhibited significantly elevated levels of anti-GFAP IgG (p < 0.001) and anti-PIT IgG (p < 0.001) compared to controls, while anti-MBP autoantibody levels remained unchanged. No significant differences were observed for any IgM autoantibody measurements. These patterns suggest that repetitive blast exposure induces a chronic, adaptive immune response rather than a short-lived acute phase. The elevated IgG autoantibodies highlight the vulnerability of astrocytes, myelin, and the hypothalamic–pituitary axis to ongoing immune-mediated injury following repeated blast insults, likely reflecting sustained blood–brain barrier disruption and neuroinflammatory processes. Our findings underscore the potential of CNS-targeted IgG autoantibodies as biomarkers of cumulative brain injury and immune dysregulation in blast-exposed populations. Further research is warranted to validate these markers in larger, more diverse cohorts, and to explore their utility in guiding interventions aimed at mitigating neuroinflammation, neuroendocrine dysfunction, and long-term neurodegenerative risks in military personnel and similarly exposed groups. [ABSTRACT FROM AUTHOR]

The goal of this study was to assess the health effects of (copper oxide nanparticles) CuO NPs on the brain structure and function in rats. Morphology results showed that the number of axons with the damaged myelin sheath in basal ganglia and the proportion of pathologically altered mitochondria in olfactory bulbs and basal ganglia had increased, while the concentration of myelin basic protein in blood serum remained unchanged. We also have observed the lower body weight gain, signs of hemolytic anemia, an increased platelet count, reduced locomotion and exploratory activity. We propose that the central nervous system and haematopoiesis are the targets for toxicity of CuO NPs administered intranasally during six weeks at the total dose of 0.45 mg/kg body weight. [ABSTRACT FROM AUTHOR]

Background and aims: The present investigation examines the impact of aerobic exercises, especially swimming and running wheel exercises, on the clinical manifestations and myelin basic protein (MBP) levels in mice with experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). MBP is critical for the formation of myelin sheaths within the nervous system, and its deterioration is linked to the pathogenesis of MS. Methods: The sample of the study consisted of 96 female C57BL/6 mice. After the EAE induction, the mice were divided into 8 groups. The animals performed two exercise protocols. Then, the brain tissue was isolated, and levels of the mentioned variables were measured via the ELISA method using specific kits. The data were analyzed statistically using one-way ANOVA. Results: Results showed that lesion scores in both exercise protocols were lower in EAE mice than those in the control groups (P=0.001); in other words, swimming and receiving interferon-beta-1 reduced MBP degradation, but the decrease was not significant (P=0.09). Additionally, running wheels reduced MBP degradation, which was statistically significant (P=0.001). Conclusion: Results suggested that using a voluntary running wheel might be a more effective exercise program than swimming in preventing MBP degradation in the brain tissues of mice with EAE. [ABSTRACT FROM AUTHOR]

Background: Preterm white matter injury (PWMI) is the most common type of brain injury in preterm infants, in which, oligodendrocyte progenitor cells (OPCs) are predominantly damaged. In this study, human OPCs (hOPCs) were administered to a fetal goat model of PWMI to examine the differentiation potential and therapeutic effects of the cells on PWMI. Methods: Preterm goat fetuses were subjected to hypoxic‐ischemia (HI) via intermittent umbilical cord occlusion (5 min × 5). Twenty million hOPCs were administered via a nasal catheter 12 h after an HI insult, and brain tissues were collected 14 or 21 days after the HI insult. Myelin basic protein (MBP) and myelin‐associated glycoprotein (MAG) were detected by immunofluorescence and western blotting techniques. The percentage of myelinated nerve fibers and g‐ratio were examined using transmission electron microscopy. Inflammatory cells were detected by immunohistochemistry. Inflammatory and neurotrophic factors were measured using enzyme‐linked immunosorbent assay. Results: Our results showed that intermittent umbilical cord occlusion induced PWMI in fetal goats. Transplanted hOPCs can survive in periventricular and subcortical white matter. Further, transplanted hOPCs expressed markers of mature oligodendrocytes (MBP and MAG) and few cells expressed markers of preoligodendrocytes (NG2 and A2B5), suggesting that these cells can differentiate into mature oligodendrocytes in the brain. In addition, hOPCs administration increased MBP and MAG levels, percentage of myelinated nerve fibers, and thickness of the myelin sheath, indicating a reduction in PWMI. Furthermore, hOPCs did not increase the inflammatory response after HI. Interestingly, hOPC administration decreased tumor necrosis factor‐alpha and increased glial‐derived neurotrophic factor and brain‐derived neurotrophic factor levels after HI, suggesting that additional mechanisms mediate the inflammatory microenvironment and neuroprotective effects. Conclusions: Exogenous hOPCs can differentiate into mature oligodendrocytes in fetal goats and alleviate HI‐induced PWMI. Transplantation of hOPCs is a promising strategy for treating PWMI. [ABSTRACT FROM AUTHOR]

Slight and hidden hearing loss in children have been linked to cognitive and social difficulties, and yet the neurobiological mechanisms behind these issues remain poorly understood. Most animal models focus on severe hearing loss, leaving the effects of hidden or slight hearing loss largely unexplored. To uncover the neural mechanisms connecting slight/hidden hearing loss to cognitive and social challenges, we induced hearing loss in young (4-week-old) Wistar rats through noise exposure. We then examined cognitive function (object recognition test) and social behavior (juvenile play behavior and social interaction). Changes in brain anatomy were assessed using cortical thickness and hippocampal size measurements, while (immuno)histochemical staining investigated neuronal circuitry maturation (myelin basic protein, parvalbumin, and perineuronal nets) and neurogenesis (doublecortin). Noise-exposed rats displayed slight high-frequency hearing loss (around 20 dB) and hidden hearing loss at other tested frequencies. This slight/hidden hearing loss was associated with impaired object recognition but did not alter social behavior. Slight/hidden hearing loss was associated with reduced myelin basic protein expression in the corpus callosum but no other alterations in cortical thickness, hippocampal size, or other markers of maturation and neurogenesis were found. These findings show that even slight/hidden hearing loss can lead to subtle brain alterations tied to cognitive deficits. This study emphasizes the need for further research to fully understand the brain changes associated with slight/hidden hearing loss and to pinpoint the mechanisms connecting these changes to behavioral deficits. This information is crucial to develop interventions to prevent the cognitive and social consequences of hearing loss. [ABSTRACT FROM AUTHOR]

Exposure to arsenic by man and animals and the resultant toxic effects are of great concern. Consequently, there is a search for medicinal plants with potential anti-toxic effects for remediation. The current study investigated the effect of Tridax procumbens (TP) (whose medicinal uses have been reported traditionally) on sodium arsenite-mediated cellular dysfunctions. Thirty-two male Wistar rats (80–100 g) were equally grouped into four. The first group (control) was administered 1 ml/kg body weight (bwt.) olive oil; the second group, 2.5 mg/kg bwt sodium arsenite (SA); the third group, 100 mg/kg bwt TP; and the fourth group, SA and TP. Oral treatment was done with TP given daily for 14 days and SA on days 7 and 14. Haematological profile, hepatic biomarkers, relative numbers of micronuclei in bone marrow cells, histological examination, and inducible nitric oxide synthase (iNOS) and myelin basic protein (MBP) expression were assessed. TP mitigates the haemotoxic and hepatotoxic effects of SA in the co-exposed group. Similarly, TP ameliorated SA-induced histological lesions in the liver, lungs, and cerebral cortex, and micronuclei formation in bone marrow cells. In the co-treated group, TP downregulated the induced expression of iNOS protein by SA in the lungs, cerebral cortex, and liver. TP upregulated MBP expression in the treated group as compared to the control. These findings suggest that TP has cytoprotective effects on SA-mediated cellular dysfunctions in Wistar rats via the suppression of clastogenicity and inflammation, and enhanced myelination and erythropoiesis. [ABSTRACT FROM AUTHOR]

Background and Purpose: The oxidant sensor transient receptor potential ankyrin 1 (TRPA1) channel expressed by Schwann cells (SCs) has recently been implicated in several models of neuropathic pain in rodents. Here we investigate whether the pro‐algesic function of Schwann cell TRPA1 is not limited to mammals by exploring the role of TRPA1 in a model of chemotherapy‐induced peripheral neuropathy (CIPN) in zebrafish larvae. Experimental Approach: We used zebrafish larvae and a mouse model to test oxaliplatin‐evoked nociceptive behaviours. We also performed a TRPA1 selective silencing in Schwann cells both in zebrafish larvae and mice to study their contribution in oxaliplatin‐induced CIPN model. Key Results: We found that zebrafish larvae and zebrafish TRPA1 (zTRPA1)‐transfected HEK293T cells respond to reactive oxygen species (ROS) with nociceptive behaviours and intracellular calcium increases, respectively. TRPA1 was found to be co‐expressed with the Schwann cell marker, SOX10, in zebrafish larvae. Oxaliplatin caused nociceptive behaviours in zebrafish larvae that were attenuated by a TRPA1 antagonist and a ROS scavenger. Oxaliplatin failed to produce mechanical allodynia in mice with Schwann cell TRPA1 selective silencing (Plp1+‐Trpa1 mice). Comparable results were observed in zebrafish larvae where TRPA1 selective silencing in Schwann cells, using the specific Schwann cell promoter myelin basic protein (MBP), attenuated oxaliplatin‐evoked nociceptive behaviours. Conclusion and Implications: These results indicate that the contribution of the oxidative stress/Schwann cell/TRPA1 pro‐allodynic pathway to neuropathic pain models seems to be conserved across the animal kingdom. [ABSTRACT FROM AUTHOR]

Aims: Cerebral small vessel diseases (SVDs) involve diverse pathologies of the brain's small blood vessels, leading to cognitive deficits. Cerebral magnetic resonance imaging (MRI) reveals white matter hyperintensities (WMHs), lacunes, microbleeds and enlarged perivascular spaces in SVD patients. Although correlations of MRI and histopathology help to understand the pathogenesis of SVD, they do not explain disease progression. Mouse models, both genetic and sporadic, are valuable for studying SVD, but their resemblance to clinical SVD is unclear. The study examined similarities and differences between mouse models of SVDs and human nonamyloid SVD specimens. Methods: We analysed four mouse models of SVD (hypertensive BPH mice, Col4a1 mutants, Notch3 mutants and Htra1−/− mice) at different stages for changes in myelin, blood‐brain barrier (BBB) markers, immune cell populations and immune activation. The observations from mouse models were compared with human SVD specimens from different regions, including the periventricular, frontal, central and occipital white matter. Postmortem MRI followed by MBP immunostaining was used to identify white matter lesions (WMLs). Results: Only Notch3 mutant and hypertensive BPH mice showed significant changes in myelin basic protein (MBP) immunostaining, correlating with MRI patterns. These changes were linked to altered microglial morphology and focal plasma protein staining around blood vessels, without peripheral immune cell infiltration. In human specimens, both normal‐appearing white matter (NAWM) and WMLs lacked peripheral cell infiltration. However, WMLs displayed altered microglial morphology, reduced myelin staining and occasional fibrinogen staining around arterioles and venules. Conclusions: Our data show that Notch3 mutants and hypertensive BPH/2J mice recapitulate several features of human SVD, including microglial activation, focal sites of demyelination and perivascular plasma protein leakage without peripheral immune cell infiltration. [ABSTRACT FROM AUTHOR]

The article explores the genetic factors influencing the prevalence and presentation of multiple sclerosis (MS) across different racial and ethnic groups. It highlights the role of genetic variation, particularly in the HLA-DRB1*15:01 allele, in MS risk and severity. The study suggests that genetic differences, ancestral lineages, and local ancestry may contribute to the observed phenotypic differences in MS across populations. The findings underscore the importance of further research into the genetic components of diverse MS phenotypes, particularly in non-European populations, to advance knowledge and promote research equity. [Extracted from the article]

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Objective: Based on the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) signaling path- way, to investigate the effect of xingnaojing injection combined with nimodipine on the recovery of neurological function in patients with hypertensive intracerebral hemorrhage (HICH). Methods: Using a random number table method, 132 patients with HICH were divided into control group (treated with nimodipine, 66 cases) and research group (treated with xingnaojing injection on the basis of control group, 66 cases). The changes of serum nerve cell factor indexes, serum SDF-1, CXCR4 levels, quality of life disease scale (SIS) score, national institutes of health stroke scale (NIHSS) score and modified Rankin scale (mRS) score were compared in two groups. Results: After 14 days of treatment, the levels of serum neuron-specific enolase (NSE), myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), SDF-1 and CXCR4 in two groups decreased, and the decrease was more significant in the research group (P<0.05). After 3 months of treatment, the NIHSS and mRS scores in two groups decreased, and research group improved more significantly(P<0.05). The scores of SIS in each dimension in two groups increased, and research group improved more significantly (P<0.05). Conclusion: Xingnaojing injection combined with nimodipine can significantly improve the prognosis of HICH patients, and promote the recovery of neuro- logical function, the mechanism may be related to the regulation of SDF-1/CXCR4 signaling pathway. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance This study was undertaken to analyze the histology underlying increased T2 signal intensity (iT2SI) in anterior temporal lobe white matter (aTLWM) epilepsy due to hippocampal sclerosis (TLE/HS).Twenty‐three patients were included: 16 with increased T2 signal in the aTLWM and seven with HS only. Magnetic resonance imaging (MRI) findings were consistent across two neuroradiologists (kappa = .89, p < .001). Quantification of neuronal cells, astrocytes, oligodendrocytes, and vacuolization in the white matter of temporal lobe specimens was performed by immunohistochemistry (neuronal nuclear antigen, glial fibrillary acidic protein, oligodendrocyte transcription factor, and basic myelin protein, respectively). Surgical specimens from TLE/HS patients with and without iT2SI in the aTLWM were compared. Samples of aTLWM were divided into three groups, according to MRI features: G1 = samples of iT2SI, G2 = samples with normal T2 signal intensity from patients without white matter imaging abnormalities, and G3 = samples with normal T2 signal intensity adjacent to areas with iT2SI.Patients with increased T2 signal had a significantly younger age at epilepsy onset (p < .035). Histological analysis revealed a higher percentage of vacuolar area in these patients (p < .004) along with a lower number of ectopic neurons (p = .042). No significant differences were found in astrocyte or oligodendrocyte counts among groups.A higher proportion of vacuoles in regions with iT2SI may be the histopathologic substrate of this signal alteration in the white matter of the temporal lobe in patients with TLE/HS. This method of quantifying vacuoles using digital image analysis proved reliable and cost‐effective. [ABSTRACT FROM AUTHOR]

Failure of myelin regeneration by oligodendrocytes contributes to progressive decline in many neurological diseases. Here, using in vitro and in vivo rodent models, functional blockade, and mouse brain demyelination, we demonstrate that Sonic hedgehog (Shh) expression in a subset of oligodendrocyte progenitor cells precedes the expression of myelin basic protein (MBP), a major myelin sheath protein. Primary cultures of rodent cortical oligodendrocytes show that Shh mRNA and protein are upregulated during oligodendrocyte maturation before the upregulation of MBP expression. Importantly, almost all MBP-positive cells are Shh positive during differentiation. During remyelination, we identify a rapid induction of Shh mRNA and peptide in oligodendroglial cells present in the demyelinated corpus callosum of mice, including a population of PDGFRα-expressing cells. Shh invalidation by an adeno-associated virus strategy demonstrates that the downregulation of Shh impairs the differentiation of oligodendrocytes in vitro and decreases MBP and myelin proteolipid protein expression in the demyelinated mouse brain at late stages of remyelination. We also report a parallel expression of Shh and MBP in oligodendroglial cells during early post-natal myelination of the mouse brain. Thus, we identify a crucial Shh signal involved in oligodendroglial cell differentiation and remyelination, with potential interest in the design of better-targeted remyelinating therapeutic strategies. [ABSTRACT FROM AUTHOR]

This study investigates the changes in hippocampal proteomic profiles during demyelination and remyelination using the cuprizone model. Employing two-dimensional gel electrophoresis and liquid chromatography-tandem mass spectrometry for protein profiling, we observed significant alterations in the expression of ketimine reductase mu-crystallin (CRYM) and protein disulfide isomerase A3 precursor (PDIA3) following exposure to and subsequent withdrawal from cuprizone. Immunohistochemical staining validated these protein expression patterns in the hippocampus, revealing that both PDIA3 and CRYM were downregulated in the hippocampal CA1 region during demyelination and upregulated during remyelination. Additionally, we explored the potential protective effects of CRYM and PDIA3 against cuprizone-induced demyelination by synthesizing cell-permeable Tat peptide-fusion proteins (Tat-CRYM and Tat-PDIA3) to facilitate their crossing through the blood–brain barrier. Our results indicated that administering Tat-CRYM and Tat-PDIA3 mitigated the reduction in proliferating cell and differentiated neuroblast counts compared to the group receiving cuprizone alone. Notably, Tat-PDIA3 demonstrated significant effects in enhancing myelin basic protein expression alongside phosphorylation of CREB in the hippocampus, suggesting its potential therapeutic role in the prevention or treatment of demyelination, and by extension, in conditions such as multiple sclerosis. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to investigate the role of high-intensity interval training (HIIT) in promoting myelin sheath recovery during the remyelination phase in cuprizone (CPZ)-induced demyelination mice and elucidate the mechanisms involving the Wnt/β-catenin pathway. Methods: After 5 weeks of a 0.2% CPZ diet to induce demyelination, a 4-week recovery phase with a normal diet was followed by HIIT intervention. Mice body weight was monitored. Morris water maze (MWM) gauged spatial cognition and memory, while the open field test (OFT) assessed anxiety levels. Luxol fast blue (LFB) staining measured demyelination, and immunofluorescence examined myelin basic protein (MBP) and platelet-derived growth factor receptor-alpha (PDGFR-α). Western blotting analyzed protein expression, including MBP, PDGFR-α, glycogen synthase kinase-3β (GSK3β), β-catenin, and p-β-catenin. Real-time PCR detected mRNA expression levels of CGT and CST. Results: HIIT promoted remyelination in demyelinating mice, enhancing spatial cognition, memory, and reducing anxiety. LFB staining indicated decreased demyelination in HIIT-treated mice. Immunofluorescence demonstrated increased MBP fluorescence intensity and PDGFR-α+ cell numbers with HIIT. Western blotting revealed HIIT reduced β-catenin levels while increasing p-β-catenin and GSK3β levels. Real-time PCR demonstrated that HIIT promoted the generation of new myelin sheaths. Additionally, the Wnt/β-catenin pathway agonist, SKL2001, decreased MBP expression but increased PDGFR-α expression. Discussion: HIIT promotes remyelination by inhibiting the Wnt/β-catenin pathway and is a promising rehabilitation training for demyelinating diseases. It provides a new theoretical basis for clinical rehabilitation and care programs. [ABSTRACT FROM AUTHOR]

Normal aging, though lacking widespread neurodegeneration, is nevertheless characterized by cognitive impairment in learning, memory, and executive function. The aged brain is spared from neuron loss, but white matter is lost and damage to myelin sheaths accumulates. This myelin damage is strongly associated with cognitive impairment. Although the cause of the myelin damage is not known, microglia dysregulation is a likely contributor. Immunologic proteins interact with microglial receptors to modulate microglia-mediated phagocytosis, which mediates myelin damage clearance and turn-over. Two such proteins, "eat me" signal C1q and "don't eat me" signal CD47, act in opposition with microglia. Both C1q and CD47 have been implicated in Multiple Sclerosis, a demyelinating disease, but whether they play a role in age-related myelin pathology is currently unknown. The present study investigates C1q and CD47 in relation to age-related myelin degeneration using multilabel immunofluorescence, RNAscope, and confocal microscopy in the cingulum bundle of male and female rhesus monkeys across the lifespan. Our findings showed significant age-related elevation in C1q localized to myelin basic protein, and this increase is associated with more severe cognitive impairment. In contrast, CD47 localization to myelin decreased in middle age and oligodendrocyte expression of CD47 RNA decreased with age. Lastly, microglia reactivity increased with age in association with the changes in C1q and CD47. Together, these results suggest disruption in the balance of "eat me" and "don't eat me" signals during normal aging, biasing microglia toward increased reactivity and phagocytosis of myelin, resulting in cognitive deficits. [ABSTRACT FROM AUTHOR]

Background: The myelin sheath ensures efficient nerve impulse transmission along the axons. Remyelination is a spontaneous process that restores axonal insulation, promoting neuroprotection and recovery after myelin damage. There is an urgent need for new pharmacological approaches to remyelination and to improve the most effective molecules. Some glucocorticoids (GC) were identified through phenotypical screens for their promyelinating properties. These GC compounds share the ability to bind the Smoothened (Smo) receptor of the Hedgehog (Hh) pathway. Gaining a deeper insight into how they modulate Smo receptor activity could guide structure-based studies to leverage the GCs' potent promyelinating activity for a more targeted approach to remyelination. Methods: Here we focused on clarifying the mechanism of action of Budesonide, a GC known to bind the Smo cysteine-rich domain (CRD) and prevent Smo translocation to the cilium in fibroblasts. Our study employed a combination of cellular, biochemical and molecular dynamics approaches. Results: We show that treating oligodendroglial cells with Budesonide promotes myelination of synthetic axons and reduces Smo CRD conformational flexibility. This inhibits the Smo-mediated canonical signaling while activating the Liver Kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) pathway, leading to Myelin basic protein (MBP) expression. Discussion: These insights pave the way for pharmacological targeting of Smo CRD to enhance oligodendrocyte precursor cells (OPCs) differentiation and improve remyelination. [ABSTRACT FROM AUTHOR]

A 6-year-old female spayed Podenco-crossbreed dog was presented with an unusual type of focal impaired awareness seizures, including sensory ataxia and postictal rest. Magnetic resonance imaging examination revealed pre- and postcontrast agent T1-weighted bilateral symmetric hyperintensities in the lentiform nuclei and globus pallidus. Repeated cerebrospinal fluid sampling showed lymphocytic pleocytosis. Cerebrospinal fluid immunoglobulin G autoantibodies to myelin basic protein (MBP) were detected by immunofluorescence examination with strong binding to myelinated fiber tracts. The absence of binding to MBP-depleted mouse brains confirmed MBP as an antigenic target. Although the patient had minor seizure episodes every 2 months, and the owners avoided seizure triggers, they refused medical treatment before presenting to the veterinarian. To the best of our knowledge, this is the first description of MBP autoantibody-positive encephalitis in a dog. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) that led to brain atrophy. The purpose of this study was to investigate the effects of pre-and post-conditioning with exercise on demyelination and brain morphology. Thirty male rats were randomly divided into five groups (n = 6 per group), consisting of a healthy control group (Control), an MS group, and three exercise groups: the group that performed the exercise protocol (running on a treadmill 5 days/week for 6 weeks) before the MS induction (EX + MS), the group that performed the exercise protocol during the MS induction (MS + EX), and the group that performed the exercise protocol before and during the MS induction (EX + MS + EX). The expression of Myelin basic protein (MBP), and demyelination in the corpus callosum and the volume, weight, length, width, and height of the brain were measured. The EX + MS + EX showed a significant increase in the expression of MBP compared to other MS groups (**p < 0.01) as well as a significant decrease in the area of demyelination of the corpus callosum compared to MS and MS + EX groups (**p < 0.01). However, there were no significant differences between the MS group and exercised groups for brain morphology. The exercise showed neuroprotective effects, as evidenced by decreased areas of demyelination and improved MBP expression. [ABSTRACT FROM AUTHOR]

Glial cell dysfunction results in myelin loss and leads to subsequent motor and cognitive deficits throughout the demyelinating disease course.Therefore, in various therapeutic approaches, significant attention has been directed toward glial-restricted progenitor (GRP) transplantation for myelin repair and remyelination, and numerous studies using exogenous GRP injection in rodent models of hypomyelinating diseases have been performed. Previously, we proposed the transplantation of canine glial-restricted progenitors (cGRPs) into the double-mutant immunodeficient, demyelinated neonatal shiverer mice (shiverer/Rag2−/−). The results of our previous study revealed the myelination of axons within the corpus callosum of transplanted animals; however, the extent of myelination and lifespan prolongation depended on the transplantation site (anterior vs. posterior). The goal of our present study was to optimize the therapeutic effect of cGRP transplantation by using a multisite injection protocol to achieve a broader dispersal of donor cells in the host and obtain better therapeutic results. Experimental analysis of cGRP graft recipients revealed a marked elevation in myelin basic protein (MBP) expression and prominent axonal myelination across the brains of shiverer mice. Interestingly, the proportion of galactosyl ceramidase (GalC) positive cells was similar between the brains of cGRP recipients and control mice, implying a natural propensity of exogenous cGRPs to generate mature, myelinating oligodendrocytes. Moreover, multisite injection of cGRPs improved mice survival as compared to non-transplanted animals. [ABSTRACT FROM AUTHOR]

[Display omitted] • We developed an aggressive multiple system atrophy-cerebellar variant mouse model. • In mice, human α-synuclein was expressed in oligodendrocytes via Tet-Off regulation. • We observed age-dependent phosphorylated α-synuclein deposition in glia and neurons. • Marked microglial and astrocytic reaction with inflammation in demyelinated lesions. • α-Synuclein oligomers spread from oligodendrocytes to astrocytes and neurons. Multiple system atrophy (MSA) is a severe α-synucleinopathy facilitated by glial reactions; the cerebellar variant (MSA-C) preferentially involves olivopontocerebellar fibres with conspicuous demyelination. A lack of aggressive models that preferentially involve olivopontocerebellar tracts in adulthood has hindered our understanding of the mechanisms of demyelination and neuroaxonal loss, and thus the development of effective treatments for MSA. We therefore aimed to develop a rapidly progressive mouse model that recaptures MSA-C pathology. We crossed Plp1 -tTA and tetO- SNCA*A53T mice to generate Plp1 -tTA::tetO- SNCA*A53T bi-transgenic mice, in which human A53T α-synuclein—a mutant protein with enhanced aggregability—was specifically produced in the oligodendrocytes of adult mice using Tet-Off regulation. These bi-transgenic mice expressed mutant α-synuclein from 8 weeks of age, when doxycycline was removed from the diet. All bi-transgenic mice presented rapidly progressive motor deterioration, with wide-based ataxic gait around 22 weeks of age and death around 30 weeks of age. They also had prominent demyelination in the brainstem/cerebellum. Double immunostaining demonstrated that myelin basic protein was markedly decreased in areas in which SM132, an axonal marker, was relatively preserved. Demyelinating lesions exhibited marked ionised calcium-binding adaptor molecule 1-, arginase-1-, and toll-like receptor 2-positive microglial reactivity and glial fibrillary acidic protein-positive astrocytic reactivity. Microarray analysis revealed a strong inflammatory response and cytokine/chemokine production in bi-transgenic mice. Neuronal nuclei-positive neuronal loss and patchy microtubule-associated protein 2-positive dendritic loss became prominent at 30 weeks of age. However, a perceived decrease in tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta in bi-transgenic mice compared with wild-type mice was not significant, even at 30 weeks of age. Wild-type, Plp1 -tTA, and tetO- SNCA*A53T mice developed neither motor deficits nor demyelination. In bi-transgenic mice, double immunostaining revealed human α-synuclein accumulation in neurite outgrowth inhibitor A (Nogo-A)-positive oligodendrocytes beginning at 9 weeks of age; its expression was further increased at 10 to 12 weeks, and these increased levels were maintained at 12, 24, and 30 weeks. In an α-synuclein-proximity ligation assay, α-synuclein oligomers first appeared in brainstem oligodendrocytes as early as 9 weeks of age; they then spread to astrocytes, neuropil, and neurons at 12 and 16 weeks of age. α-Synuclein oligomers in the brainstem neuropil were most abundant at 16 weeks of age and decreased thereafter; however, those in Purkinje cells successively increased until 30 weeks of age. Double immunostaining revealed the presence of phosphorylated α-synuclein in Nogo-A-positive oligodendrocytes in the brainstem/cerebellum as early as 9 weeks of age. In quantitative assessments, phosphorylated α-synuclein gradually and successively accumulated at 12, 24, and 30 weeks in bi-transgenic mice. By contrast, no phosphorylated α-synuclein was detected in wild-type, tetO- SNCA*A53T , or Plp1 -tTA mice at any age examined. Pronounced demyelination and tubulin polymerisation, promoting protein-positive oligodendrocytic loss, was closely associated with phosphorylated α-synuclein aggregates at 24 and 30 weeks of age. Early inhibition of mutant α-synuclein expression by doxycycline diet at 23 weeks led to fully recovered demyelination; inhibition at 27 weeks led to persistent demyelination with glial reactions, despite resolving phosphorylated α-synuclein aggregates. In conclusion, our bi-transgenic mice exhibited progressively increasing demyelination and neuroaxonal loss in the brainstem/cerebellum, with rapidly progressive motor deterioration in adulthood. These mice showed marked microglial and astrocytic reactions with inflammation that was closely associated with phosphorylated α-synuclein aggregates. These features closely mimic human MSA-C pathology. Notably, our model is the first to suggest that α-synuclein oligomers may spread from oligodendrocytes to neurons in transgenic mice with human α-synuclein expression in oligodendrocytes. This model of MSA is therefore particularly useful for elucidating the in vivo mechanisms of α-synuclein spreading from glia to neurons, and for developing therapies that target glial reactions and/or α-synuclein oligomer spreading and aggregate formation in MSA. [ABSTRACT FROM AUTHOR]

Inhibition of autophagy is one of the hallmarks of the SARS-CoV-2 infection. Recently it was reported that SARS-CoV-2 protein ORF3a inhibits fusion of autophagosomes with lysosomes via interaction with VPS39 thus preventing binding of homotypic fusion and protein sorting (HOPS) complex to RAB7 GTPase. Here we report that myelin basic protein (MBP), a major structural component of the myelin sheath, binds ORF3a and is colocalized with it in mammalian cells. Co-expression of MBP with ORF3a restores autophagy in mammalian cells, inhibited by viral protein. Our data suggest that basic charge of MBP drives suppression of ORF3a-induced autophagy inhibition as its deaminated variants lost ability to bind ORF3a and counteract autophagy blockade. These results together with our recent findings, indicating that MBP interacts with structural components of the vesicle transport machinery-synaptosomal-associated protein 23 (SNAP23), vesicle-associated membrane protein 3 (VAMP3) and Sec1/Munc18-1 family members, may suggest protective role of the MBP in terms of the maintaining of protein traffic and autophagosome–lysosome fusion machinery in oligodendrocytes during SARS-CoV-2 infection. Finally, our data may indicate that deimination of MBP observed in the patients with multiple sclerosis (MS) may contribute to the previously reported worser outcomes of COVID-19 and increase of post-COVID-19 neurologic symptoms in patients with MS. [Display omitted] • MBP interacts with SARS-CoV-2 proteins N, E, nsp9 and nsp16 in mammalian cells. • MBP interacts and colocalizes with SARS-CoV-2 protein ORF3a in mammalian cells. • MBP counteracts ORF3a-mediated failure of the autophagy machinery. • Basic charge of MBP drives suppression of ORF3a-induced autophagy inhibition. [ABSTRACT FROM AUTHOR]

The neurodevelopmental toxicity of anesthetics has been confirmed repeatedly, and esketamine is now widely used in pediatric surgeries. Oligodendrocyte precursor cells (OPCs) evolved into mature oligodendrocytes (OLs) and formed myeline sheath during the early brain development. In this study, we investigated whether esketamine exposure interrupted development of OPCs and induced hypomyelination in rats. Further we explored the roles of PI3K/Akt phosphorylation in OPCs development and myelination. Sprague Dawley rats with different ages (postnatal day (P) 1, 3, 7 and 12) were exposed to 40mg/kg esketamine. Progesterone treatment was given (16 mg/kg per day for 3 days) 24 h after esketamine exposure via the intraperitoneal route. Corpus callosum tissues were collected at P8 or P14 for western blot and immunofluorescence analyses. Esketamine exposure at P7 and P12 significantly reduced myelin basic protein (MBP) expression and CC1+ OLs number in corpus callosum. Esketamine exposure at P7 not only aggravated the mature OLs apoptosis, also decreased the OPCs proliferation and differentiation, which was related with dephosphorylation of PI3K/Akt. Progesterone was able to promote OPCs differentiation and ameliorate esketamine-induced hypomyelination by enhancing PI3K/Akt phosphorylation. Stage-dependent abnormality of OPCs/OLs after esketamine leads to the esketamine-induced hypomyelination. Esketamine interrupted OPCs evolution via PI3K/Akt signaling pathway, which can be ameliorated by progesterone. [ABSTRACT FROM AUTHOR]

Healthy brain development hinges on proper myelination, with disruption contributing to a wide array of neurological disorders. Immunohistochemical analysis of myelin basic protein (MBP) is a fundamental technique for investigating myelination and related disorders. However, despite decades of MBP research, detailed accounts of normal MBP progression in the developing mouse brain have been lacking. This study aims to address this gap by providing a detailed spatiotemporal account of MBP distribution across 13 developmental ages from postnatal day 2 to 60. We used an optimized immunohistochemistry protocol to overcome the challenges of myelin’s unique lipid-rich composition, enabling more consistent staining across diverse brain structures and developmental stages, offering a robust baseline for typical myelination patterns, and enabling comparisons with pathological models. To support and potentially accelerate research into myelination disorders, we have made >1,400 high-resolution micrographs accessible online under the Creative Commons license.

Abstract Alterations in the white matter have been implicated in schizophrenia. Myelin basic protein (MBP), a component of the myelin sheath, in the cerebrospinal fluid (CSF) has been suggested as a biomarker for white matter damage in demyelinating diseases. This prompted us to examine the CSF‐MBP levels in patients with schizophrenia. We analyzed the CSF‐MBP levels in 152 patients with schizophrenia and 117 age‐ and sex‐matched controls. A significant positive correlation between age and CSF‐MBP levels was observed both in the patients (p

Objective: To analyze the expression of pediatric Critical Case scoring (PCIS) combined with serum microRNA-125b and granulocyte colony stimulating factor (G-CSF) in children with viral encephalitis and its correlation with prognosis. Methods: 105 children with viral encephalitis admitted to our hospital from January 2022 to June 2023 were selected to be included in the observation group, and another 105 healthy physical examination children in the same period were selected to be included in the control group. All enrollees were subjected to PCIS scoring, and serum microRNA-125b and G-CSF expression levels were detected to analyze the variability of PCIS scoring, serum microRNA-125b, and G-CSF expression levels in children with viral encephalitis of different severity and the relationship with indicators of cerebral damage in the cerebrospinal fluid; with a follow-up of 6 months, the poor prognosis was recorded, and a multifactorial logistic regression and a multifactor logistic regression were used to measure the prognosis. Factor logistic regression and subject work characteristics (ROC) curves were used to analyze the relationship between PCIS score, serum microRNA-125b, G-CSF and poor prognosis. Results: The PCIS score of observation group was lower than that of control group, and the expression levels of serum microRNA-125b and G-CSF were higher than those of control group (P<0.05). Of the 105 children with viral encephalitis, 40 were severe and 65 were non-severe cases. The PCIS score of the critical group was lower than that of the non-critical group, and the expression levels of serum microRNA-125b and G-CSF were higher than those of the non-critical group (P<0.05). By Pearson correlation analysis, the children with viral encephalitis PCIS score, serum microRNA-125b, the expression level of G-CSF and myelin basic protein (MBP) in cerebrospinal fluid, brain type of creatine kinase (CK-BB), neuron specific enolization enzyme (NSE) expression levels were positively correlated (P<0.05). The multi-factor Logistic regression, PCIS score, serum microRNA-125b and G-CSF is children with viral encephalitis is an independent predictor of poor prognosis (P<0.05). The ROC curve analysis, PCIS score, serum microRNA-125b joint G-CSF prediction of prognosis of children with viral encephalitis, AUC is 0.923. Conclusion: PCIS score, serum microRNA-125b, and G-CSF are all associated with severity of illness in children with viral encephalitis, and the combination improves the level of prediction of poor prognosis. [ABSTRACT FROM AUTHOR]

[Display omitted] • ● SPS induced NLRP3 inflammasome activation in the hippocampus of rats. • ● The hippocampal region of rats with PTSD showed increased myelin content. • ● MCC950 alleviated myelin alterations in the hippocampal region of PTSD rats. Inflammatory and myelin changes may contribute to the pathophysiology of post-traumatic stress disorder (PTSD). The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3), a brain inflammasome, is activated in the hippocampus of mice with PTSD. In other psychiatric disorders, NLRP3 expression has been associated with axonal myelination and demyelination. However, the association between NLRP3 and myelin in rats with PTSD remains unclear. Therefore, this study aims to investigate the relationship between the NLRP3 inflammasome and myelin in the hippocampus of rats with PTSD. A rat model of post-traumatic stress disorder was established using the single-prolonged stress (SPS) approach. Hippocampal tissues were collected for the detection of NLRP3 inflammasome-associated proteins and myelin basic protein at 3, 7, and 14 days after SPS. To further explore the relationship between NLRP3 and myelin, the NLRP3-specific inhibitor MCC950 was administered intraperitoneally to rats starting 72 h before SPS, and then alterations in NLRP3 inflammasome-associated proteins and myelin were observed in the PTSD and control groups. We found that NLRP3 and downstream related proteins were activated in the hippocampus of rats 3 days after SPS, and the myelin content in the hippocampus increased after SPS stress. MCC950 reduced the expression of NLRP3-related pathway proteins, improved anxiety behaviour and spatial learning memory impairment, and inhibited the increase in myelin content in the hippocampal region of rats after SPS. In conclusion the study indicates that NLRP3 has a significant role in the hippocampal region of rats with PTSD. Inhibition of the NLRP3 inflammasome could be a potential target for treating PTSD. [ABSTRACT FROM AUTHOR]

Previously, we described the mechanisms of development of autoimmune encephalomyelitis (EAE) in 3-month-old C57BL/6, Th, and 2D2 mice. The faster and more profound spontaneous development of EAE with the achievement of deeper pathology occurs in hybrid 2D2/Th mice. Here, the cellular and immunological analysis of EAE development in 2D2/Th mice was carried out. In Th, 2D2, and 2D2/Th mice, the development of EAE is associated with a change in the differentiation profile of hemopoietic bone marrow stem cells, which, in 2D2/Th, differs significantly from 2D2 and Th mice. Hybrid 2D2/Th mice demonstrate a significant difference in these changes in all strains of mice, leading to the production of antibodies with catalytic activities, known as abzymes, against self-antigens: myelin oligodendrocyte glycoprotein (MOG), DNA, myelin basic protein (MBP), and five histones (H1–H4) hydrolyze these antigens. There is also the proliferation of B and T lymphocytes in different organs (blood, bone marrow, thymus, spleen, lymph nodes). The patterns of changes in the concentration of antibodies and the relative activity of abzymes during the spontaneous development of EAE in the hydrolysis of these immunogens are significantly or radically different for the three lines of mice: Th, 2D2, and 2D2/Th. Several factors may play an essential role in the acceleration of EAE in 2D2/Th mice. The treatment of mice with MOG accelerates the development of EAE pathology. In the initial period of EAE development, the concentration of anti-MOG antibodies in 2D2/Th is significantly higher than in Th (29.1-fold) and 2D2 (11.7-fold). As shown earlier, antibodies with DNase activity penetrate cellular and nuclear membranes and activate cell apoptosis, stimulating autoimmune processes. In the initial period of EAE development, the concentration of anti-DNA antibodies in 2D2/Th hybrids is higher than in Th (4.6-fold) and 2D2 (25.7-fold); only 2D2/Th mice exhibited a very strong 10.6-fold increase in the DNase activity of IgGs during the development of EAE. Free histones in the blood are cytotoxic and stimulate the development of autoimmune diseases. Only in 2D2/Th mice, during different periods of EAE development, was a sharp increase in the anti-antibody activity in the hydrolysis of some histones observed. [ABSTRACT FROM AUTHOR]