Frontiers In Cellular Neuroscience[JOURNAL]
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200 papers
Liquid-liquid phase separation couples MKRN2-mediated ubiquitination of CSDE1 with neurodevelopmental disorders.
Wang Z, Han Y, Yang P … +5 more , Jia C, Li C, Yuan S, Wei P, Hu R
Front Cell Neurosci · 2026 · PMID 41757349 · Full text
BACKGROUND: Makorin-2 (MKRN2) is an E3 ubiquitin ligase involved in multiple biological processes, yet its role in neurological disorders remains poorly understood. This study aims to elucidate how MKRN2 regulates the RN...
BACKGROUND: Makorin-2 (MKRN2) is an E3 ubiquitin ligase involved in multiple biological processes, yet its role in neurological disorders remains poorly understood. This study aims to elucidate how MKRN2 regulates the RNA-binding protein CSDE1-a molecule linked to autism-related genes-and to explore the functional implications of this interaction in neurodevelopment. METHODS: Using mass-spectrometry screening, we identified CSDE1 as a direct substrate of MKRN2. Ubiquitination sites were validated through mutagenesis of conserved lysine residues. Liquid-liquid phase separation (LLPS) assays were performed in HEK293 and SH-SY5Y cells, and behavioral phenotypes were assessed in -knockout mice. Statistical analyses included appropriate tests for comparing ubiquitination levels, condensate formation, and social behavior outcomes. RESULTS: MKRN2 mediates CSDE1 ubiquitination at four lysine residues (K81, K91, K208, K727). Deletion of or mutation of these sites abolished ubiquitination. MKRN2 and CSDE1 formed co-localized condensates via LLPS, which was disrupted by functional impairment of either protein. -knockout mice exhibited sex-specific social abnormalities-increased sociability in males and social withdrawal in females-recapitulating autism-spectrum disorder (ASD) heterogeneity. We further identified and , ASD-associated mRNAs, as ubiquitination-dependent targets of CSDE1, linking aberrant condensate dynamics to synaptic plasticity deficits. CONCLUSION: Our study reveals an LLPS-coupled ubiquitination mechanism by which MKRN2 regulates CSDE1, providing a novel molecular pathway underlying neurodevelopmental disorders. These findings offer new insights for understanding and treating neurological diseases such as ASD.
Microglial heterogeneity: influence of human 2D, 3D, and co-culture models on gene expression and immune function.
Etebar F, White AR, Quek H
Front Cell Neurosci · 2026 · PMID 41757348 · Full text
Microglia, the resident immune cells of the central nervous system, exhibit substantial phenotypic and functional diversity shaped by local microenvironmental cues. While advanced human microglial models exist, the infl...
Microglia, the resident immune cells of the central nervous system, exhibit substantial phenotypic and functional diversity shaped by local microenvironmental cues. While advanced human microglial models exist, the influence of culture dimensionality and cellular context on microglial state composition remains poorly defined. Here, we analyzed single-cell RNA sequencing datasets from human monocyte-derived microglia (MDMi) cultured under two-dimensional (2D) and three-dimensional (3D) monoculture, as well as 3D neural-glial co-culture conditions. Across platforms, four microglial states were identified, including interferon (IFN)-responsive, chemokine-enriched, metabolically active, and proliferative states, with pronounced environment-dependent transcriptional shifts. 2D cultures were dominated by -responsive microglia characterized by elevated IFITM2 and IFITM3 expression, whereas 3D systems supported greater cellular diversity, including expanded metabolic programs and chemokine remodeling. Co-culture further increased proliferative microglia and induced immune-communication signatures involving , , and pathways. Pseudotime analysis revealed a largely linear trajectory in 2D cultures, but branching differentiation paths in 3D and co-culture systems, consistent with enhanced microglial heterogeneity. Benchmarking against human microglial reference signatures demonstrated broader and stronger overlap in 3D-based models, with homeostatic and disease-associated modules engaged in a context-specific manner. These findings demonstrate that culture architecture is a major determinant of microglial identity and immune responsiveness; and highlight the value of single-cell datasets to uncover previously underappreciated microglial states with relevance to human neuroimmune biology.
Modeling pediatric brain tumors with human stem cells.
Burket N, Augustine T, Tailor J
Front Cell Neurosci · 2026 · PMID 41757347 · Full text
With recent advances in stem cell technology, there has been an expansion of human stem and progenitor cell models of pediatric brain tumors, including use of human pluripotent and embryonic stem cells both in organoid c...
With recent advances in stem cell technology, there has been an expansion of human stem and progenitor cell models of pediatric brain tumors, including use of human pluripotent and embryonic stem cells both in organoid cultures and following xenotransplantation in mice. In this review, we discuss the current approaches to modelling pediatric brain cancers using stem cells. While brain tumors describe a broad set of disease entities, we focus on glioma, medulloblastoma and ependymoma, as these are not only the most common malignant brain tumor types but also have the most stem cell models currently available. We examine human stem cell-based modeling approaches and discuss the biological questions that are being addressed using these state-of-the-art tools. Specifically, we focus on the unique advantage of using these cells to understand the functional consequences of gene mutations and their downstream growth-promoting pathways within the cell in a human context. These approaches are needed to ascertain the key players that are functionally relevant in the initiation and propagation of these tumors at the gene and protein level and to identify new drug targets. Moreover, human stem cell-based modeling approaches may complement studies in genetically engineered mouse models to address fundamental questions in tumor biology, particularly the early stages of tumorigenesis.
Distinct cytokine-producing dendritic cell profiles in females and males with major depressive disorder.
Boller AL, Freff J, Bast M … +5 more , Schwarte K, Dannlowski U, Baune BT, Scheu S, Alferink J
Front Cell Neurosci · 2026 · PMID 41737535 · Full text
INTRODUCTION: Major depressive disorder (MDD) is a revalent and disabling condition increasingly associated with immune dysregulation. Dendritic cells (DCs) are key immune sentinels that shape inflammatory responses and...
INTRODUCTION: Major depressive disorder (MDD) is a revalent and disabling condition increasingly associated with immune dysregulation. Dendritic cells (DCs) are key immune sentinels that shape inflammatory responses and T-cell polarization, including Th17 pathways implicated in depression-related mild inflammation. Given well-documented sex differences in immune responses and cytokine profiles in MDD, differential DC activation may represent a mechanistic link between sex-associated immune cell profiles in depression. However, DCs remain insufficiently characterized in MDD. METHODS: We performed an exploratory study using flow cytometry-based immunophenotyping to assess circulating DC subsets, including CD1c and CD141 conventional DCs (cDCs), plasmacytoid DCs (pDCs), and their cytokine profiles in individuals with MDD ( = 55) and healthy controls (HC, = 32). Stratification by depression severity and sex, together with correlation and multivariate linear regression analyses, and cluster analysis, was used to examine associations between DC subsets and depressive symptom severity in females and males. RESULTS: Stratification by HAM-D17 scores revealed reduced counts of pDCs and increased frequencies of CD11c cDCs in the peripheral blood (PB) of severely depressed participants compared to HC or mildly depressed patients, respectively. Regarding cytokine-producing DCs, sex-stratified analyses showed that frequencies of IL-23 cDCs were elevated and symptom-associated only in females with MDD compared to sex-matched controls, whereas frequencies of TNF, IL-1β, and IL-6 cDCs were selectively increased in depressed males. Cluster analyses identified distinct female- and male-specific DC subset patterns distinguishing individuals with MDD from HC. Multivariate linear regression revealed a significant predictive contribution of cytokine-producing DCs, together with age and BMI, in females but not in males. DISCUSSION: These findings demonstrate sex-specific alterations in cytokine-producing DCs in MDD and a strong association between IL-23 cDCs and depressive symptom severity, suggesting a key role for these cells in immune dysregulation, particularly in females with depression.
Reprogramming brain-resident macrophages: from disease drivers to therapeutic allies in neurological disorders.
Zhao P, Li SY, Liu Q … +6 more , Peng XC, Liu L, Yang FY, Wang C, Qian F, Tang FR
Front Cell Neurosci · 2026 · PMID 41737534 · Full text
Brain-resident macrophages (BRMs), including microglia and border-associated macrophages (BAMs), are the core immune sentinels of the central nervous system (CNS). They originate from early embryonic yolk sac and fetal l...
Brain-resident macrophages (BRMs), including microglia and border-associated macrophages (BAMs), are the core immune sentinels of the central nervous system (CNS). They originate from early embryonic yolk sac and fetal liver progenitors and maintain their population throughout life via self-renewal. During neurodevelopment, microglia maintain neural network homeostasis by phagocytosing apoptotic neural precursors and pruning synaptic connections. In adulthood, they rapidly respond to infection, injury, or protein aggregation, which can both promote repair and exacerbate neurotoxicity. BAMs, located in the meninges, perivascular spaces, and choroid plexus, play a key role in boundary homeostasis and peripheral immune signal surveillance. Recent studies reveal that BRMs exhibit dual roles in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), as well as ischemic stroke, traumatic brain injury, and radiation-induced brain injury: they can protect neurons by clearing pathological proteins or cellular debris, but persistent inflammatory responses may drive neurodegeneration. In AD, microglia clear Aβ plaques via triggering receptor expressed on myeloid cells 2 (TREM2) and ADGRG1 signaling, while BAMs regulate synaptic damage and cerebrovascular function through CD36-ROS and SPP1 pathways. In PD and HD, BRMs contribute to -synuclein- and mutant huntingtin-related inflammatory responses. In MS, BRMs modulate the pro-/anti-inflammatory balance through antigen presentation and cytokine signaling. Based on these mechanisms, therapeutic strategies targeting BRM functions are emerging, including NLRP3 inflammasome inhibitors, TREM2 agonists, and interventions promoting microglial neuroprotective phenotypes. Future approaches aiming to precisely modulate BRM plasticity and their interactions with the peripheral immune system may transform these immune sentinels from "disease drivers" to "therapeutic allies," offering novel strategies for treating neurodegenerative diseases and brain injuries.
Editorial: Multiscale brain modelling.
D'Angelo E
Front Cell Neurosci · 2026 · PMID 41737533 · Full text
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β-amyloid and β-amyloid precursor protein synthesis and processing: effects of exercise and exercise-related injury.
Zhen W, Xing Y, Li Y … +3 more , Hao J, Kong L, Zhen H
Front Cell Neurosci · 2026 · PMID 41737532 · Full text
During the processing and assembly of β-amyloid precursor protein (APP), the amyloidogenic pathway represents a crucial component of Alzheimer's disease (AD) pathogenesis. The non-amyloidogenic pathway does not generate...
During the processing and assembly of β-amyloid precursor protein (APP), the amyloidogenic pathway represents a crucial component of Alzheimer's disease (AD) pathogenesis. The non-amyloidogenic pathway does not generate toxic Aβ. For a long time, research has delved deeply into both pathways, elucidating numerous important details and mechanisms within these processes. Scientists and clinicians have sought to design effective therapeutic interventions based on these mechanisms. However, this endeavor has encountered numerous setbacks, resulting in no currently available drugs capable of reversing AD progression. Regarding APP processing and assembly, we are curious whether daily activities influence these processes. We focus on exercise as a daily activity, systematically exploring whether it affects APP processing and assembly and the underlying mechanisms. Furthermore, we examine alterations in APP processing and assembly in exercise-related injury disorders, summarizing and analyzing existing research. We discuss promising future research directions, aiming to contribute to preventing adverse outcomes following exercise-related injuries.
Editorial: Novel approaches to foster brain plasticity in neurodevelopmental and neurodegenerative disorders.
Allegra Mascaro AL, Baroncelli L, Cambiaghi M
Front Cell Neurosci · 2025 · PMID 41727712 · Full text
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Bridging cognitive reserve and cerebellar networks: counteracting brain damage in patients with Alzheimer's disease at different clinical stages.
Serra L, Rizzuti M, Bonarota S … +7 more , Caruso G, Di Domenico C, Mancini M, Giove F, Caltagirone C, Gelfo F, Petrosini L
Front Cell Neurosci · 2026 · PMID 41726382 · Full text
INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by cognitive decline and brain atrophy. Recent evidence shows that the cerebellum also undergoes structural and functional...
INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by cognitive decline and brain atrophy. Recent evidence shows that the cerebellum also undergoes structural and functional alterations. The concept of cognitive reserve (CR) explains individual resilience to brain pathology, while the hypothesis of cerebellar cognitive reserve (CbCR) sustains an enhanced activity in cerebellar networks at rest and a more efficient recruitment of accessory areas during cognitive tasks. This study investigated structural connectivity changes in cerebellar-cortical networks across the AD continuum. METHODS: A total of 179 participants were enrolled, encompassing 46 AD patients, 51 with amnestic mild cognitive impairment (aMCI), 46 with subjective cognitive decline (SCD), and 36 healthy subjects (HS). CR was defined by years of formal education. Whole-brain T1-weighted images were analysed using source-based morphometry (SBM) to identify patterns of grey matter concentration (GMC) covariance. RESULTS: Three main networks were identified: the cerebellum-basal ganglia-cingulum (CBGC), the anterior cerebellum-supplementary motor arearetrosplenial cortex (ACSMARC), and the posterior cerebellum-orbitofrontal cortex (PCOC), with the cerebellum as the only common structure. All networks showed progressive reductions in GMC covariance along the clinical continuum, with a specific pattern of GMC reduction according to diagnostic groups. Importantly, CbCR modulated connectivity within all networks, with higher levels associated with preserved structural integrity and better cognitive outcomes. DISCUSSION: These findings provide evidence of progressive cerebellar-cortical disconnection in AD pathology and highlight cerebellar reserve as a potential protective factor, suggesting that the CbCR assessment and specific interventions tailored to the cerebellar cognitive functions may help delay the cognitive decline.
Recent progress in chronic pain-related negative emotions and cognitive dysfunction: insights into the mechanisms underlying neural circuitry.
Hu FX, Wu HY, Wang Y … +2 more , Zhang YL, Cui WQ
Front Cell Neurosci · 2026 · PMID 41726381 · Full text
Pain is a complex sensory and affective experience that is frequently accompanied by comorbid conditions such as anxiety, depression, fear, and cognitive dysfunction, collectively exacerbating patient suffering and disea...
Pain is a complex sensory and affective experience that is frequently accompanied by comorbid conditions such as anxiety, depression, fear, and cognitive dysfunction, collectively exacerbating patient suffering and disease burden. Despite significant advancements in pain research, the mechanisms underlying chronic pain and its related negative emotions remain inadequately understood. The cerebral cortex, lateral habenula (LHb), thalamus, amygdala, parabrachial nucleus (PBN), hippocampus, and locus coeruleus (LC) are widely associated with chronic pain, chronic pain-related negative emotions, and cognitive dysfunction. In this review, we summarize recent research on the functions of various brain nuclei and their subregions in chronic pain and related negative emotions and cognitive dysfunction from the perspective of neural circuits. By delineating these circuit-level mechanisms, we aim to provide insights that may inform the development of more effective strategies for the clinical diagnosis and treatment of chronic pain and comorbid emotional and cognitive dysfunctions.
The integration of plasma non-target metabolomics and lipidomics analysis for the discovery of global developmental delay/intellectual disability biomarkers.
Chen B, Chen S, Xiong J … +4 more , Kessi M, Peng J, Yin F, He F
Front Cell Neurosci · 2026 · PMID 41717644 · Full text
BACKGROUND: This study aimed to identify metabolic signatures and potential biomarkers for global developmental delay (GDD) and intellectual disability (ID) using plasma metabolomics and lipidomics. The research sought t...
BACKGROUND: This study aimed to identify metabolic signatures and potential biomarkers for global developmental delay (GDD) and intellectual disability (ID) using plasma metabolomics and lipidomics. The research sought to evaluate the feasibility of these methods for early identification and to explore the underlying metabolic pathways associated with GDD/ID. METHODS: A liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)-based method integrated with multivariate data analysis was employed to comprehensively characterize plasma metabolomics and lipidomics profiles in children diagnosed with GDD/ID compared to typically developing (TD) children. The study focused on identifying distinct metabolites and lipids that could differentiate GDD/ID from TD children. RESULTS: The analysis revealed that a combination of 11 metabolites and lipids could effectively discriminate between GDD/ID and TD children. Receiver operating characteristic (ROC) analysis identified several potential biomarkers for GDD/ID. In positive ion mode, glycerophosphocholine (AUC = 0.899) and sphinganine (AUC = 0.859) showed diagnostic potential. Negative ion mode analysis revealed five biomarkers, notably 2-ketohexanoic acid (AUC = 0.912) and N-acetyl-L-aspartic acid (AUC = 0.870). Lipidomics analysis highlighted two high-performance biomarkers: diacylglycerol (DAG) (16:0/16:0) (AUC = 0.956) and DAG (16:0/18:0) (AUC = 0.949). Key metabolic pathways associated with GDD/ID included D-glutamine, D-glutamate, alanine, aspartate, glutamate, sphingolipid, histidine, arginine, and proline metabolisms. Furthermore, lysine metabolic pathways, including degradation and biosynthesis, as well as aminoacyl-tRNA biosynthesis, were implicated in GDD/ID pathogenesis. CONCLUSION: This study identified putative biomarkers and metabolic pathways associated with GDD/ID, highlighting the potential of combined plasma metabolomics and lipidomics for early screening of GDD/ID and providing tentative insights into its pathophysiology. The biomarkers show strong diagnostic performance as screening tools, but future studies are needed to validate their prognostic value and clinical utility in multi-center cohorts.
Enhancing oligodendrocytes generation and myelin renewal by vitamin C mitigate Parkinson-relevant phenotypes in a murine model of Parkinson's disease.
Cui S, Wang S, Liu M … +3 more , Zou Q, Cai Z, Ma J
Front Cell Neurosci · 2026 · PMID 41717643 · Full text
Parkinson's disease (PD) is a major neurodegenerative disease with an increasing global prevalence. In addition to progressive dopaminergic neurons degeneration, emerging evidence implicates oligodendrocyte (OL) dysfunct...
Parkinson's disease (PD) is a major neurodegenerative disease with an increasing global prevalence. In addition to progressive dopaminergic neurons degeneration, emerging evidence implicates oligodendrocyte (OL) dysfunction and impaired myelin also contribute to PD pathogenesis. Here, we observed a significant reduction of myelin basic protein (MBP) and the number of OLs in the MPTP-induced chronic PD mouse model. Vitamin C (VC) has been reported to promote myelin regeneration in the demyelination mouse model, though its underlying mechanism remains unclear. Therefore, this study investigated the therapeutic effects of VC in the mouse model of PD by the enhancement of OPC-to-oligodendrocyte differentiation and myelin renewal. Using oligodendrocyte precursor cell (OPC) differentiation systems, we confirmed that VC markedly enhanced the differentiation of OPC to OL. In MPTP-induced PD mice, VC treatment not only ameliorated myelin damage but also protected dopaminergic neurons, and led to a significant improvement in PD-relevant behavioral phenotype. Mechanistically, the effects of VC are mediated through the activation of Ten-eleven translocation (TET) enzymes, which promotes DNA hydroxymethylation and subsequent expression of genes essential for OL differentiation. Taken together, these findings suggest that promoting OPC-to-oligodendrocyte differentiation and myelin repair by VC could serve as a promising therapeutic strategy in PD.
Nrg1 regulates cortical wiring and motor recovery upon traumatic injury.
González-Manteiga A, Navarro-González C, Rodríguez-Prieto Á … +2 more , Zavaglia MV, Fazzari P
Front Cell Neurosci · 2026 · PMID 41717642 · Full text
INTRODUCTION: Traumatic brain injury (TBI) is a leading cause of disability, yet molecular mechanisms supporting cortical repair remain poorly defined. While Neuregulin 1 (Nrg1) is essential for cortical development, its...
INTRODUCTION: Traumatic brain injury (TBI) is a leading cause of disability, yet molecular mechanisms supporting cortical repair remain poorly defined. While Neuregulin 1 (Nrg1) is essential for cortical development, its role in traumatic cortical injury in adults is unclear. METHODS: To circumvent developmental confounds, we used an inducible conditional Nrg1 knockout in the adult mouse and subjected it to controlled cortical damage (CCD) in the motor cortex. We combined high-resolution adeno-associated viral tracing of callosal projections with comprehensive behavioral, histological, and molecular analyses. RESULTS: Nrg1 deletion led to significant impairments in structural connectivity and motor recovery, which were markedly exacerbated in mature mice, indicating a critical role for Nrg1 in adult cortical repair. Mechanistically, our data indicate that Nrg1 promotes this plasticity through intracellular domain (ICD) signaling, acting cell-autonomously to enhance axonal outgrowth in neuronal cultures. Furthermore, loss of Nrg1 was associated with altered perineuronal net (PNN) structure and increased neuroinflammation at the lesion site. DISCUSSION: These findings identify endogenous Nrg1 as a key regulator of structural preservation and functional recovery after cortical injury, highlighting Nrg1 signaling as a potential target to enhance cortical plasticity following trauma.
Editorial: Intercellular communication in chronic neuroinflammatory diseases.
Potokar M, Jorgačevski J, Matsuse D … +1 more , Vicario N
Front Cell Neurosci · 2026 · PMID 41717641 · Full text
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TLR3 activation in astrocytes attenuates the nigrostriatal pathway degeneration in rodent models of Parkinson's disease.
Jeong J, Won SY, Chung YC … +3 more , Shin WH, Jin BK, Park ES
Front Cell Neurosci · 2026 · PMID 41717640 · Full text
Toll-like receptor 3 (TLR3) is classically known for mediating inflammatory pathways in Parkinson's disease (PD). However, the role of TLR3 in nigrostriatal degeneration in PD remains unclear. Here, we observed that TLR3...
Toll-like receptor 3 (TLR3) is classically known for mediating inflammatory pathways in Parkinson's disease (PD). However, the role of TLR3 in nigrostriatal degeneration in PD remains unclear. Here, we observed that TLR3 is predominantly expressed on astrocytes in the substantia nigra in both human PD brain and in rat PD models induced by intra-MFB injection of 1-methyl-4-phenylpyridinium (MPP). Interestingly, Poly I: C, an activator of TLR3, significantly induced TLR3 expression on astrocytes. Treatment with Poly I: C markedly attenuated nigral dopamine neuron death in the PD rat models. The survival of dopamine neurons was accompanied by the production of ciliary neurotrophic factor and vascular endothelial growth factor-B on astrocytes in Poly I: C-treated PD rats. The attenuation of dopamine neuron death was also observed in the Poly I: C-treated AAV2-hα-syn-A53T-induced rat PD model. Our findings suggest that activating TLR3 in astrocytes could be a potential therapeutic strategy for attenuating PD progression.
Retraction: NaHS protects against the impairments induced by oxygen-glucose deprivation in different ages of primary hippocampal neurons.
Frontiers Editorial Office
Front Cell Neurosci · 2026 · PMID 41710029 · Full text
[This retracts the article DOI: 10.3389/fncel.2017.00067.].
[This retracts the article DOI: 10.3389/fncel.2017.00067.].
Photobiomodulation (PBM) irradiation enhances the therapeutic potential of hMSC spheroids for neural repair.
Chang SY, Hong N, Choi JE … +2 more , Ahn JC, Lee MY
Front Cell Neurosci · 2026 · PMID 41696652 · Full text
Neural regeneration remains a critical goal in regenerative medicine, especially for treating central nervous system injuries such as stroke, spinal cord injury, and neurodegenerative diseases. Mesenchymal stem cells (MS...
Neural regeneration remains a critical goal in regenerative medicine, especially for treating central nervous system injuries such as stroke, spinal cord injury, and neurodegenerative diseases. Mesenchymal stem cells (MSCs) have shown therapeutic potential through their capacity for differentiation and paracrine signaling; however, their clinical application is limited by low survival and engraftment rates. In this study, we investigated whether the therapeutic efficacy of human MSC (hMSC) spheroids could be enhanced through photobiomodulation (PBM). hMSCs were aggregated into three-dimensional spheroids and divided into four experimental groups: (1) untreated control spheroids, (2) spheroids treated with 660 nm PBM, (3) spheroids treated with 850 nm PBM, and (4) spheroids co-cultured with primary rat cortical neurons subjected to oxidative stress using hydrogen peroxide (H₂O₂). The PBM groups were exposed to red (660 nm) or near-infrared (NIR; 850 nm) light for 10 min. Neuronal viability and axonal regeneration were assessed. Our results demonstrated that PBM-treated hMSC spheroids significantly increased neuronal survival and axonal outgrowth compared to H₂O₂-only controls, particularly under high oxidative stress conditions. Notably, spheroids treated with 850 nm PBM exhibited the most robust neuroprotective effects. These findings suggest that PBM enhances mitochondrial activity and the secretion of neurotrophic factors by hMSC spheroids, thereby promoting neuroregeneration. This combinatorial strategy integrating PBM with 3D stem cell spheroid culture offers a promising avenue for developing advanced stem cell therapies for neurological disorders.
Local synthesis and function of neuro-estrogen and neuro-androgen: impact on the hippocampus-related cognition and neuronal plasticity.
Kawato S, Hojo Y, Soma M … +3 more , Horie S, Saito M, Ogiue-Ikeda M
Front Cell Neurosci · 2025 · PMID 41685091 · Full text
Brain sex neurosteroids have been attracted much attention, because the brain itself can synthesizes a sufficient amount of sex neurosteroids independent of circulating sex steroids. Local synthesis and action of neuro-e...
Brain sex neurosteroids have been attracted much attention, because the brain itself can synthesizes a sufficient amount of sex neurosteroids independent of circulating sex steroids. Local synthesis and action of neuro-estrogen [such as neuro-estradiol (nE2)] and neuro-androgen [such as neuro-testosterone (nT) and neuro-dihydrotestosterone (nDHT)] have become recognized as key factors in modulation of synaptic plasticity, cognitive performance, and protection of aging dependent decline of neurological functions. Unlike circulating sex steroids, these locally synthesized sex neurosteroids can directly and rapidly modulate neuronal synapses and induce potent effects on learning and memory. The properties of local neurocrine systems are significantly different from those of classical neuroendocrine systems dependent on the hypothalamic-pituitary-gonadal axis. For example, in the hippocampus, not only neuro-androgen (nT and nDHT) but also nE2 have higher concentrations than testis-derived circulating androgen (T and DHT) and ovary-derived circulating E2 (cir-E2). In addition, male nE2 concentration is higher than female nE2 at both adult stage and newborn stage during which brain masculinization occurs. Over the past decades, numerous experimental results and interpretations of sex neurosteroids have been shown. However, in several cases, these results and interpretations are mutually conflicting, and a unified understanding has not yet been achieved. Therefore, we here deeply discuss several critical and important issues toward solving complex problems to understand. We focus the following issues. First (A) Local synthesis of nE2, nT and nDHT, with particular attention to their concentrations, synthesis pathways and sex differences in rodents. Higher nE2 concentration in male hippocampus than in female in adult stage. Then (B) Comparison of modulation of long-term potentiation (LTP) by nE2 and nDHT. Stimulatory effects of nE2 on LTP which are mediated by membrane estrogen receptor ER and protein kinase signaling. Inhibitory effects of nDHT on LTP which are mediated by membrane androgen receptor AR. Third (C) Both nE2 and nDHT show the same rapid increases in dendritic spines. Their effects on spinogenesis are very different from their effects on LTP. Fourth (D) Rapid effects of nE2 and nT on cognitive behavior. Male signaling pathway may be more complex than female signaling pathway. Finally (E) Aging-dependent cognitive decline which is dependent on decrease of nT in male and nE2 in female. T-replacement therapy of male patients shows improvement in spatial cognitive decline. E2-replacement therapy improves female cognitive decline.
Neuronal activity drives PCDH9 cleavage and nuclear translocation to coordinate structural and functional remodeling.
Miozzo F, Zambrano Avendano A, Caso MG … +5 more , Valentino B, Hirano S, Murru L, Moretto E, Passafaro M
Front Cell Neurosci · 2025 · PMID 41685090 · Full text
Protocadherins are key regulators of neurodevelopment and synaptic function, acting not only as adhesion molecules but also as synaptic hubs for intracellular signaling. Here, we uncover a novel activity-dependent signal...
Protocadherins are key regulators of neurodevelopment and synaptic function, acting not only as adhesion molecules but also as synaptic hubs for intracellular signaling. Here, we uncover a novel activity-dependent signaling pathway for , a protocadherin linked to Autism Spectrum Disorder and Major Depressive Disorder. By combining biochemical and immunohistochemistry approaches on neuronal cultures, we show that neuronal activity triggers Matrix Metalloproteases (MMP)-dependent cleavage of PCDH9, generating a C-terminal fragment (CTF) that translocates to the nucleus. PCDH9 CTF overexpression promotes dendritic growth, increases spine density, and concomitantly strengthens excitatory synaptic transmission. These findings identify PCDH9 CTF as a novel activity-dependent signaling molecule that links synaptic activity to structural remodeling and functional modulation, suggesting a new mechanism by which synaptic activity shapes neuronal properties.
Oridonin attenuates TLR4-driven inflammation and autophagy in LPS-stimulated enteric glial cells: an and analysis.
Nemutlu Samur D, Boyacı A, Maytalman E
Front Cell Neurosci · 2026 · PMID 41684728 · Full text
INTRODUCTION: Enteric glial cells (EGCs) are key regulators of gut-brain axis immunity, and their excessive activation contributes to intestinal inflammation and neuroimmune disturbances implicated in early Parkinson's d...
INTRODUCTION: Enteric glial cells (EGCs) are key regulators of gut-brain axis immunity, and their excessive activation contributes to intestinal inflammation and neuroimmune disturbances implicated in early Parkinson's disease. Oridonin, a diterpenoid compound with known anti-inflammatory and autophagy-modulating properties, has not been extensively studied in peripheral glial models. Here, we investigated the effects of oridonin on TLR4-mediated inflammatory signaling and autophagy responses in LPS-stimulated EGCs, with molecular docking used as a supportive, hypothesis-generating approach. METHODS: Rat-derived EGCs were exposed to LPS (10 μg/mL) to induce glial activation. Cells were treated with oridonin (1-5 μM) with or without the selective TLR4 inhibitor TAK-242. mRNA levels of TLR4, S100B, LC3, and beclin-1 were quantified by RT-qPCR, while caspase-1 and IL-1β protein levels were assessed by ELISA. Molecular docking was performed to explore potential interactions of oridonin and TAK-242 with the TLR4 receptor complex. RESULTS: LPS significantly increased TLR4 and S100B expression and upregulated the autophagy markers beclin-1 and LC3. Oridonin dose-dependently suppressed LPS-induced upregulation of TLR4 and S100B and attenuated the elevation of autophagy-related transcripts. Docking studies suggested that oridonin and TAK-242 may interact with regulatory regions of the TLR4 complex, including surface-exposed sites on the TLR4-MD-2 ectodomain and distinct sub-pockets within the intracellular TIR domain, with oridonin exhibiting a stronger predicted binding affinity. Although LPS increased TLR4 mRNA, it elicited only a modest increase in caspase-1 levels and no significant change in IL-1β levels, consistent with incomplete inflammasome activation. Whereas TAK-242 alone did not fully suppress IL-1β, combined treatment with oridonin reduced cytokine levels more effectively, suggesting complementary downstream modulation rather than direct receptor-level synergy. DISCUSSION: Oridonin exerts powerful anti-inflammatory and autophagy-modulating effects in EGCs by inhibiting TLR4-driven signaling, normalizing excessive autophagic responses, and limiting IL-1β output. Its dual capacity to suppress both upstream (TLR4/S100B) and downstream (caspase-1/IL-1β) components of the inflammatory cascade preserves EGC homeostasis under endotoxin stress. These findings highlight oridonin as a potential modulator of peripheral glial inflammation and support further investigation of its therapeutic potential in gut-brain axis disorders.
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