A novel class of active immunotherapy, consisting of proprietary T-helper peptide linked to a B-cell epitope, is being developed to target tau in Alzheimer's disease (AD). These experimental therapies generate antibodies that have demonstrated binding to pathological tau in vitro, and efficacy in cell-based tau aggregation assays comparable to monoclonal antibodies. Here, we report the ability of one such tau-targeting immunotherapy, p5555kb, to prevent the progression of tau pathology using two distinct mouse models. P301L mice were immunized with p5555kb and showed greater survival rates at 210 days than saline-inoculated control mice. The efficacy of p5555kb against tau seeding in vivo was assessed by injecting C57BL6 mice with tau fibrils purified from post-mortem human AD brain tissue. Immunization with p5555kb significantly reduced the amount of tau inclusions detected by immunohistochemistry at 9 months post-injection, as compared to saline inoculation. This study demonstrates that p5555kb is effective at inducing functional tau-targeting antibodies, which prevented the onset of adverse phenotypes associated with tau pathology in vitro and in vivo.

Vessel-associated microglia (VAM) are an integral part of the neurovascular unit and have recently been implicated in the pathophysiology of cerebrovascular injury and blood-brain barrier (BBB) leakiness in Alzheimer's disease (AD). In this neuropathological study, we explored the hypothesis that the distribution and activation of VAM are altered in AD in the presence of systemic infection, associated with cerebrovascular dysfunction. We studied VAM density in the temporal cortex and underlying white matter from AD and age-matched controls with and without terminal systemic infection (SI) (n = 15 per group). The area of VAM labelled with microglial markers (Iba1, HLA-DR, CD68) was quantified in proximity to CD31-labelled microvessels within three predefined regions: contact VAM, proximity <15 μm, and parenchymal >15 μm. The relationships between VAM and previously measured brain cytokine levels and biochemical markers of cerebral perfusion (MAG:PLP1, endothelin-1) and BBB leakiness (VEGF-A and fibrinogen), were explored in a subset of cases. Compared to controls, the relative area of Iba1+ VAM was higher in SI and in AD. The area of HLA-DR+ VAM was higher in AD only. The area of Iba1+ VAM that expressed CD68, a marker of phagocytosis, was higher in both AD and AD + SI. Iba1+ and HLA-DR+ VAM correlated inversely with anti-inflammatory cytokines (IL-10, IL-23) in AD and positively with pro-inflammatory cytokines (IL-6, IL-23, GM-CSF, IL-17) in AD + SI. Iba1+ VAM density correlated positively with endothelin-1, VEGF-A and fibrinogen in controls. HLA-DR+ VAM density correlated positively with Aβ in both controls and AD, and inversely with PDGFRβ and VCAM-1 in AD. Our data reveal the distribution of VAM is elevated in AD, and altered in the presence of systemic infection, which together are likely to be independent and synergistic contributors to cerebrovascular dysfunction in AD.

The meninges, which originate from the neural crest cells and mesoderm, play crucial roles in the formation, protection, and homeostasis of the central nervous system. Meningiomas, which arise from the meninges, are the most common primary intracranial tumors, and their recurrence and malignant transformation represent major clinical challenges. Recent studies have identified mesenchymal stromal cell- and fibroblast-expressing Linx paralogue (Meflin), as being expressed in the meninges, but its role in meningeal development and meningioma pathophysiology remains poorly understood. In this study, we investigated the expression patterns of Meflin during meningeal development and in meningioma tissues. Meflin expression was detected in the head of a Meflin reporter mouse line at approximately 11.5 days of embryonic life, suggesting its involvement in early meningeal development. Lineage-tracing experiments revealed that Meflin mRNA cells contribute to the postnatal formation and turnover of meningeal cells in adulthood, indicating their role in meningeal homeostasis. In human meningioma samples, Meflin expression was observed in normal meningeal cells and almost all tumor samples, with higher expression levels correlating with higher histological grades and increased recurrence rates. Analysis of a publicly available meningioma gene expression dataset revealed that tumors with high Meflin expression exhibited enhanced WNT ligand biogenesis and trafficking compared with tumors expressing low levels of Meflin. Furthermore, single-cell RNA sequencing analysis confirmed this finding and revealed elevated WNT6 expression specifically in clusters of Meflin-high tumor cells, highlighting a potential link between Meflin and WNT signaling activation in meningioma progression. Thus, this study provides novel insights into the role of Meflin in meningeal development and meningioma pathophysiology.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by the degeneration of motor neurons and the presence of TAR DNA-binding protein 43 (TDP-43) aggregation in the brain. Dyslipidemia is a common feature of ALS, and increasing evidence indicates that lipid dysregulation in the central nervous system underlies ALS pathology. Sphingomyelin is a sphingolipid that is highly enriched in the human brain. However, very little is known about changes in sphingomyelin in the context of ALS brain. We therefore undertook a comprehensive analysis of sphingomyelin in the disease-affected motor cortex and disease-unaffected cerebellum in sporadic ALS with TDP-43 pathology using liquid chromatography-mass spectrometry. We found that sphingomyelin was significantly increased in the ALS motor cortex compared to controls and was strongly associated with disease duration. In contrast, sphingomyelin was unaltered in the cerebellum. The increase in sphingomyelin was associated with an upregulation of ATP-binding cassette subfamily A member 8 (ABCA8), a sphingomyelin transporter, only in the motor cortex of ALS. Importantly, both sphingomyelin and ABCA8 were associated with TDP-43 only in the motor cortex. These results suggest that increases in sphingomyelin and ABCA8 could be a protective response against TDP-43 pathology.

There is a paucity of autopsy-based studies providing detailed neuropathological characteristics of fatal hypothermia cases, particularly in trauma-associated cases. Hence, this study investigated 2054 serial autopsy cases in which histopathological examination of all organs, including the brain, could be performed. We identified 168 cases (75 female and 93 male patients) of fatal hypothermia and examined the clinical and neuropathological characteristics in these cases. Patients aged ≥65 years constituted 80% of the cohort (135 cases). Cognitive impairment (CI) was identified in 39% of cases with available clinical histories, and approximately half of these cases were presumed to have developed hypothermia while wandering, based on clinical history and the circumstances of discovery. Alzheimer's disease was the most commonly identified pathology, affecting 40% of the total and approximately two-thirds of patients aged ≥80 years. CI caused by multiple pathologies, especially two, was more frequently observed than by a single pathology. The most common manner of exposure to cold temperatures was accidents (120 cases), including 35 cases with multiple traumatic injuries, most likely resulting from falls. In these cases, the trauma was considered the primary cause of immobility, leading to subsequent exposure to cold environments. Importantly, 30 (86%) of these trauma-associated cases showed one or more neuropathological conditions, and CI was documented in 13, with four presumed to have fallen while wandering. Notable neuropathological manifestations were also observed in eight of the 33 cases of patients aged less than 65 years. Our results demonstrate that neurodegenerative diseases, especially Alzheimer's disease, are underlying conditions in fatal hypothermia in the elderly and in relatively younger individuals, suggesting that they may contribute to its onset. These findings highlight the necessity for comprehensive neuropathological examination in all forensic autopsy cases of hypothermia.

This study leverages x-ray phase-contrast tomography (XPCT) for detailed analysis of neurodegenerative diseases, focusing on the three-dimensional (3D) visualization and quantification of neuropathological features within fixed human postmortem tissue. XPCT with synchrotron radiation offers micrometer and even sub-micron resolution, enabling us to examine intra- and extraneuronal aggregates and inclusions such as Lewy bodies (LBs), granulovacuolar degeneration (GvD), Hirano bodies (HBs), neurofibrillary tangles (NFTs), β-amyloid plaques, and vascular amyloid deposits in three dimensions. In the reconstructions, we identified the highest electron densities in Hirano and LBs, while NFTs exhibited no significant increase in XPCT contrast. Using cutting-edge high-resolution x-ray synchrotron beamlines, we were now able to detect even detect subcellular differences in electron densities found in GvD. Small-scale inhomogeneities of the electron density were also detected in LBs, potentially relating to inclusions of organelles. Additionally, we reveal here a peculiar 3D geometry of HBs and demonstrate the co-occurrence with GvD in the same neuron. These findings underscore the potential of XPCT as a powerful, label-free tool for spatially resolved neuropathological investigations, opening new avenues for the systematic 3D characterization of inclusions and aggregates in neurodegeneration.

Astrocytes contribute in critical ways to the pathophysiology of epilepsy not only through trophic support but also through the regulation of neuronal excitability by modulating glutamate, γ-aminobutyric acid (GABA), adenosine triphosphate (ATP), and adenosine levels. Calponin-3 is an actin-binding protein that is enriched in the brain. We have previously reported that increased calponin-3 expression is correlated with epileptic seizures. In the present study, we revealed that in the hippocampus of epileptic mice models, increased calponin-3 protein expression was correlated with the expression of the astrocytic marker glial fibrillary acidic protein (GFAP). Calponin-3 overexpression in the hippocampus significantly increased susceptibility to epileptic seizures, whereas calponin-3 downregulation was associated with reduced spontaneous recurrent seizures in mice. Furthermore, changes in calponin-3 levels corresponded to astrocyte activation in both mice and cultured human astrocytes and were associated with changes in the protein levels of adenosine kinase (ADK) and equilibrative nucleoside transporter 1 (ENT1), which are two key regulators of adenosine metabolism that have been shown to play critical roles in epileptogenesis. Collectively, our findings suggest that calponin-3 may regulate astrocyte-mediated adenosine metabolism and could represent a potential therapeutic target for epilepsy.

The fifth edition of the WHO classification of CNS Tumors (WHO CNS5) has revised the diagnostic and grading criteria for Adult-type Diffuse Gliomas (ADGs) by integrating molecular parameters with histologic features. Conducting molecular testing for most ADGs is now crucial in fulfilling the WHO CNS5 diagnostic criteria. However, due to additional costs and technical barriers, implementing molecular diagnostics is often not feasible in Low-Income Countries (LICs) and Lower Middle-Income Countries (LMICs). Therefore, practical approaches are needed for diagnosis in resource-restrained settings. Hence, the Asian Oceanian Society of Neuropathology (AOSNP), through the 'ADAPTR' (Adapting Diagnostic Approaches for Practical Taxonomy in Resource-Restrained Regions) initiative, aimed to provide resource-stratified recommendations for diagnosing ADGs based on available resources while adhering to the WHO guidelines as much as possible. ADAPTR identified different resource levels (RLs) of diagnostic pathology services, ranging from RL I to RL V, with RL I to RL IV being applicable to the LMICs, and provides recommendations for a 'Histology-oriented integrated diagnosis format' for each tumor type at different RLs. In addition, diagnostic flow charts for ADGs have been generated to suit these RLs. The emphasis is mainly on using histopathological approaches with immunohistochemistry, while molecular testing recommendation is categorized as 'can be considered', 'highly recommended' or 'obligatory', to reach the next level diagnosis. In each RL, either a WHO CNS5 diagnosis with an accompanying CNS WHO grade or an ADAPTR descriptive diagnosis with an associated ADAPTR histologic grade is provided, depending on the context. ADAPTR recommendations are therefore a practical adaptation of the WHO CNS5 guidelines that will suit routine diagnostic practices in resource-restrained regions.

Vasculitic neuropathy remains challenging to diagnose and monitor because of its heterogeneous clinical and laboratory presentation. Blood-based biomarkers indicating nerve damage could serve as an additional diagnostic tool to ensure early diagnosis, precise therapeutic monitoring, and a more targeted anti-inflammatory treatment. A potential marker for this purpose is neurofilament light chain (NfL), a marker of neuroaxonal damage that is used as a biomarker in several diseases of the central and peripheral nervous system. NfL has also been suggested to reflect disease activity in patients with vasculitic neuropathy. However, its biodynamics and link to degeneration of peripheral nerve tissue remain unconfirmed. To investigate the usefulness of NfL as a marker of peripheral nerve damage in this context, we retrospectively assembled a cohort of 35 patients undergoing sural nerve biopsies (including patients with vasculitic neuropathy and other neuropathies). We then measured NfL in serum samples cryoarchived at the time of biopsy and correlated NfL levels with histological parameters. For our histological analysis, we quantified parameters of acute axonal degeneration and chronic axonal loss using a combination of manual, threshold-based, and supervised learning-based analyses. We found a significant positive correlation between parameters of acute axonal degeneration and serum-NfL levels that persisted after adjusting for age and concomitant central nervous system disease. We did not find a similar correlation with parameters of chronic axonal loss quantified in nerve biopsies. These findings support the value of NfL as a marker for acute axonal degeneration in patients with vasculitic neuropathy.

Focal cortical dysplasia (FCD) is a neurodevelopmental malformation that often manifests as medically refractory epilepsy. A key histological hallmark of FCD type II is the presence of cytomegalic dysmorphic neurons (CDNs), which are considered to be major contributors to cortical network hyperexcitability. However, the relatively low frequency of CDNs within resected lesions has challenged their unbiased molecular characterization. Here, we leverage deep learning approaches to objectively map key anatomical compartments of FCD IIb and guide regional spatial transcriptomic profiling. Using this approach, we generate an anatomical transcriptional catalog of type IIb FCD, and uncover non-canonical markers of signaling and neurotransmitter pathways in CDNs that may serve as new therapeutic targets for this debilitating disorder.

Glycosylation is the most common form of post-translational modification in the brain and becomes significantly altered in the context of neurodegeneration. One notable alteration is an enrichment of terminal sialic acid (SA) modifications. Previous studies provide evidence of increased sialylation on microglia, the innate immune cell of the brain, in Alzheimer's disease (AD), particularly near amyloid beta plaques. Yet, there is little understanding of the relationship between SA and other amyloid beta-related diseases like Cerebral Amyloid Angiopathy (CAA). Nearly half of all AD cases have CAA; thus, it is critical to understand the relationship between amyloid pathology and SA modifications. The present study aimed to overcome this gap in knowledge by investigating sialylation patterns in AD cases with CAA compared with CAA-negative AD cases and amyloid-negative control cases. The localization of SA modifications was investigated in the frontal cortex of 30 post-mortem cases with or without diagnoses of AD and/or CAA. Quantitative digital pathology analyses were used to determine regional SA differences in parenchymal and leptomeningeal blood vessels. First, we found no difference in intravascular amyloid-beta levels between the parenchymal and leptomeningeal vessels of AD with CAA cases, suggesting no regional differences in this amyloid aggregation. Next, there was a visual increase in microglia sialylation surrounding parenchymal blood vessels in the CAA cases. Notably, there were significant differences in intravascular SA levels across the three comparison groups. AD cases with CAA had significantly greater sialylation levels in both the parenchymal and leptomeningeal vessels compared with the AD-only and control groups. This is a novel finding that supports the consideration of glycosylation changes that contribute to worse pathological outcomes in AD with CAA.

To bridge between detailed post-mortem neuropathological assessments and Magnetic Resonance Imaging (MRI), we have created and share a three-dimensional (3D) account of an entire human brain with an intermediate Alzheimer's disease neuropathologic change. We combined multimodal imaging, using cryosectioning, histology, immunocytochemistry, and quantitative ultra-high field 7 Tesla (T) magnetic resonance imaging (MRI) at submillimeter resolution. Amyloid-β and phosphorylated-tau immunoreactivity, cell soma, and nerve fibers were visualized, together with quantitative MR parameters. All data were coaligned with at 200 μm resolution and are openly shared. The use of whole-brain sections allows for a detailed assessment of neuropathological alterations, revealing clear differences between the left and right hemispheres in terms of pathological load of amyloid-β and phosphorylated-tau in a single brain showing Alzheimer's disease neuropathologic change. This resource opens the door for a combination of detailed correlations between neuroimaging and neuropathological microscopy observations, as well as for detailed MRI validation.

Intracranial mesenchymal tumors (IMTs) with FET::CREB fusion are newly recognized molecular entities, provisionally classified into subgroups A and B. Although Group B has been partially characterized, the clinicopathological and molecular heterogeneity of Group A remains poorly defined. This study aimed to conduct an integrated analysis of 6 newly diagnosed and 20 previously reported IMTs with FET::CREB fusion. Notably, Group A was further stratified into two distinct entities A1 and A2 based on unsupervised methylation profiling. Compared to Group A1, Group A2 demonstrated significantly shorter progression-free survival (PFS), a higher proportion of male patients, and less frequent occurrence of myxoid-rich stroma. Amplification of 10p15.3 was frequently observed in Group A2. Furthermore, GLUT-1 could serve as a potential diagnostic indicator in IMTs with FET::CREB fusion. Overall, we identified a new subgroup of IMTs with FET::CREB fusion with poor PFS and distinct clinicopathological and molecular features, offering actionable insights to refine therapeutic strategies and improve risk stratification in this emerging diagnostic category.

Phenotypic changes in microglia have been linked to multiple neurological conditions, such as dementia, Parkinson's disease, stroke and traumatic brain injury. Consistent identification and classification of microglia is essential in understanding potential links with neurological diseases. Currently, there are several ways by which the microglial population and morphology are assessed, including manually or using open-source image analysis platforms, such as ImageJ. A microglial classification module for the HALO digital pathology platform has been developed for this purpose but has not yet been validated within the literature. The current study therefore conducted a comparison of the performance of this HALO module to manual microglial analysis and to automated analysis via ImageJ using both human and rat brain tissue. In 5 μm thick human tissue, total and activated microglia/mm counted by HALO showed strong positive correlations with both manual and ImageJ counts. HALO did not differ from the other methods for total microglia counts; however, Halo did differ from both manual and ImageJ methods in the number of activated microglia detected within the substantia nigra. In 20 μm rat tissue, total counts derived from HALO showed moderate positive correlations with both manual and ImageJ counting; however, activated counts on Halo were not positively correlated with any method. To our knowledge, this is the first study to systematically compare the Halo module to other common methods of microglia analysis. When applied to 5 μm tissue, the Halo module is comparable to manual counting and to automated analysis on ImageJ. However, when analyzing thicker tissue, Halo struggles to perform in line with these other methods, particularly for counts of activated microglia, likely due to increased cell density and the morphological complexity of microglia. These results highlight the importance of carefully tailoring image analysis parameters on automated counting methods to suit the needs of the tissue.

Nitro-oleic acid (OA-NO) is an endogenous peroxisome proliferator-activated receptor-γ (PPARγ) ligand and can activate this receptor under both physiological and pathological conditions. In this study, we explore the role and molecular mechanisms of OA-NO in maintaining blood-brain barrier (BBB) integrity and enhancing neurovascular function during ischemic stroke, with a particular emphasis on the activation of endothelial PPARγ signaling pathways. Endothelial cell-selective PPARγ conditional knockout (EC-PPARγ cKO) and wild-type (WT) mice underwent 1 h middle cerebral artery occlusion (MCAO) with 1-7 days of reperfusion. Mice were treated with oleic acid (OA) or OA-NO (5 mg/kg) via tail vein 2 h after MCAO. Neurobehavioral deficits were assessed on days 3, 5, and 7 after MCAO. Neuroinflammation and BBB function were assessed on days 1 or 2 after MCAO by immunohistochemistry, RT-qPCR, or Western blot analysis. Compared to OA controls, intravenous administration of OA-NO led to reduced BBB leakage in ischemic brains, as indicated by a significant decrease in the extravasation of BBB tracers. This reduction in BBB leakage was also almost abolished in the EC-PPARγ cKO mice. Furthermore, OA-NO treatment reduced brain infarction in stroke mice, but this protective effect was completely reversed in the EC-PPARγ cKO mice. Interestingly, OA-NO treatment promoted a shift towards an anti-inflammatory microglial phenotype (M2) in the peri-infarct regions of WT mice, but not in EC-PPARγ cKO mice. Mechanistically, OA-NO increased levels of major endothelial tight junction proteins in WT mice but not in EC-PPARγ cKO mice following ischemic stroke. These findings suggest that OA-NO activation of endothelial PPARγ signaling cascade attenuates neurovascular injury after ischemic stroke.

The Consortium to Inform Molecular and Practical Approaches to Central Nervous System Tumor Taxonomy (cIMPACT-NOW) updates provide guidelines for the diagnosis of central nervous system (CNS) tumors and suggestions for future World Health Organization (WHO) classification. Following publication of the fifth edition WHO Classification of CNS Tumors (WHO CNS5) in 2021, the cIMPACT-NOW working group "Clarification" reviewed WHO CNS5 and prioritized two topics for further elucidation: (a) distinction of Glioblastoma, IDH-wildtype from Diffuse pediatric-type high-grade glioma, H3-wildtype, and IDH-wildtype and (b) clarification of subgroups of posterior fossa (PF) ependymal tumors. Recommendations regarding the IDH- and H3-wildtype diffuse high-grade gliomas include: (1) use caution assigning CNS WHO grade 4 (diagnosis of Glioblastoma, IDH-wildtype) to a "TERT promoter only", histologically low-grade, IDH-wildtype tumor; (2) EGFR gene amplification and +7/-10 chromosome copy number alterations should not be used as solitary defining features for diagnosing high-grade gliomas as Glioblastoma, IDH-wildtype in patients <40 years of age; (3) Diffuse pediatric-type high-grade glioma, H3-wildtype, and IDH-wildtype should be considered in the differential diagnosis in adults, especially those <40 years of age; (4) PDGFRA alteration, EGFR alteration, or MYCN amplification count as key molecular features of Diffuse pediatric-type high-grade glioma, H3-wildtype, and IDH-wildtype only in patients <25 years. Guidelines for improved diagnosis of posterior fossa ependymal tumors include: (1) immunohistochemical demonstration of nuclear EZHIP supports classification as PF group A ependymoma; (2) a PF ependymoma with retained nuclear H3 K27me3 expression and no nuclear EZHIP overexpression for which DNA methylation profiling is not performed should be considered as PF ependymoma, "not otherwise specified"; (3) for emerging tumors not included in WHO CNS5, "not elsewhere classified" (NEC) can be added to the diagnosis. Of note, these recommendations are not formal changes to the WHO definitions and diagnostic criteria but are intended to provide diagnostic guidance in advance of WHO CNS6.

The type C variant (TDP-C) of FTLD-TDP exhibits unique features, not shared by types A and B, namely the invariable and frequently asymmetric predilection for the anterior temporal lobes (ATL). Depending on the direction of hemispheric asymmetry, the associated clinical features include word comprehension impairment, associative agnosia, and behavioral abnormalities. Current research on TDP-C aims to explore the factors that underlie the selective targeting of the ATL and, more specifically, the cellular details that undermine the behavioral and cognitive functions of this region. Abnormal TDP-C neurites have recently been shown to represent heterodimers with annexin A11 (ANXA11). This feature, not shared by TDP-A or -B, may explain the unique predilection of TDP-C for the ATL. To further explore the subcellular distribution of the pathology, paraffin-embedded sections were stained using fluorescent antibodies for the dendritic marker MAP2 and phosphorylated TDP-43 (pTDP) or ANXA11. Results indicated that approximately half of pTDP/ANXA11 neurites co-localized with MAP2. The actual overlap during life may be much higher but decreased at autopsy through dendritic loss due to prolonged neurodegeneration. The potentially selective and progressive dendritic pathology of TDP-C, quite unique among neurodegenerative entities, may underlie the distinctive perturbation of cortical integrative computations.

Multiple sclerosis (MS) is a chronic neuroinflammatory disease that progresses to a stage marked by irreversible neurological decline and widespread neurodegeneration. Necroptosis, a regulated form of cell death primarily triggered by tumor necrosis factor (TNF), has been implicated in neuronal loss in progressive MS. The Endosomal Sorting Complex Required for Transport (ESCRT) machinery, essential for plasma membrane repair and vesicle trafficking, is known to counteract necroptosis in non-neural cells. In this study, we investigated whether ESCRT dysfunction contributes to neurodegeneration in the MS cortex. We identified a significant dysregulation of ESCRT-III complex components, particularly VPS4B and CHMP2A, in neurons of MS cortical grey matter. This dysregulation correlated with reduced neuronal density and increased meningeal inflammation. Notably, both demyelinated and normal-appearing grey matter showed decreased VPS4B, while CHMP2A loss was more restricted to areas of demyelination. These findings suggest that impaired ESCRT-III function may increase neuronal vulnerability to necroptosis and contribute to disease progression in MS. Our results highlight a novel pathway linking neuroinflammation, ESCRT dysfunction, and neuronal death, with potential therapeutic implications for neuroprotection in progressive MS.

Sphingolipids are essential, complex lipids that are abundant in the cell membranes of eukaryotic cells, particularly concentrated in the myelin and neuronal membranes of the central nervous system (CNS). These lipids are crucial components of the cell membrane, affecting their structure and fluidity, and thus regulating various biological processes, including signal transduction, cell differentiation, apoptosis, and autophagy. The metabolic pathways of sphingolipids are highly complex and conserved, and this metabolic process can produce multiple metabolites. Metabolites such as ceramide (Cer) and sphingosine-1-phosphate (S1P) are vital in CNS signaling, affecting neurodevelopment, myelination, and synaptic plasticity. Thus, disruption of sphingolipid metabolism is closely related to neurological disorders. This article provides the latest studies concerning the known features of sphingolipid and sphingolipid metabolism, highlighting its physiological and pathological roles in the CNS.