Late-life depression (LLD) with high prevalence accelerates cognitive impairment and becomes a risk factor for dementia, yet the pathogenesis of LLD is still largely unclear. Delineating the neuromolecular mechanism of LLD is of great significance to its etiology, early diagnosis, and precision treatment. This study included 35 patients with LLD and 41 age-matched healthy controls (HCs). Brain entropy (BEN) and functional connectivity (FC) were used to assess the abnormalities in brain functional system irregularity and couplings in LLD, using resting-state functional magnetic resonance imaging. Additionally, transcriptome and neurotransmitter data were employed to investigate the neuromolecular mechanisms underlying these changes. Compared with HCs, patients with LLD exhibited significantly reduced BEN in the temporoparietal junction (TPJ) and decreased FC between TPJ and the middle frontal gyrus (MFG). Moreover, the changes of BEN were closely associated with the genes' expression profiles, which were involved in endocannabinoid, adrenergic, oxytocin, and cGMP-PKG signaling, glutamatergic, GABAergic, dopaminergic, cholinergic, serotonergic synapses, long-term potentiation, and long-term depression. We also found that the changes of BEN and FC were correlated with neurotransmitterreceptor distribution patterns of serotonin, histamine, acetylcholine, and dopamine. Reduced BEN of TPJ in LLD indicates impaired regional information-processing complexity, potentially driving persistent cognitive deficits and abnormal negative-emotion handling, even in early LLD without overt clinical symptoms. Decreased TPJ-MFG FC disrupts brain network synchronization, weakening MFG-mediated emotion regulation and cognition, and possibly elevating the risk of suicidal ideation. Some genes, such as PRKACA/PRKACB, GNAI1, MAPK-ERK, PLA2G4A, and LXN, along with neurotransmitter receptors, contribute to a more comprehensive understanding of LLD. Altered brain entropy and connectivity in the TPJ-MFG circuit and related neurobiomolecules may underlie the pathogenesis of LLD and provide predictive value for its diagnosis and treatment. Our study highlights the important role of the TPJ-MFG circuit in the neuropathology of LLD and links the macroscopic functional abnormalities with transcriptome and neurotransmitter to establish the molecular basis. Our findings contribute to understanding the neurobiological basis of LLD and may facilitate future precision therapy.
CBD is widely studied for its stress-reduction and cognitive-enhancing properties, but its effects on hippocampal molecular organisation under physiological settings are unknown. Acute and long-term intraperitoneal CBD treatment at different doses was tested on hippocampus gene expression, circulating corticosterone, and behavioural performance in C57BL/6J mice. Short-term administration did not induce detectable transcriptional changes. In contrast, long-term treatment with 10 mg/kg CBD, but not lower or higher doses, resulted in significant hippocampal transcriptional remodelling. Overrepresentation analysis showed coordinated control of mitochondrial oxidative phosphorylation genes, particularly numerous respiratory chain complex I components, and purine and nucleotide metabolic pathways. Shared mitochondrial respiratory genes, not classical disease-associated effectors, enriched KEGG categories for neurodegeneration and retrograde endocannabinoid signalling. The endocrine profile showed a temporary increase in circulating corticosterone after short-term exposure, but long-term dosing decreased it. Behavioural effects were modest and limited across paradigms. These results show that long-term administration of an intermediate CBD dose alters subsets of genes related to coordinated bioenergetic and nucleotide-related transcriptional adaptation in the hippocampus, which modulates endocrine stress markers but does not disrupt behaviour. The data suggest that chronic CBD exposure may cause metabolic recalibration in stress-sensitive brain circuits rather than acute neuromolecular reprogramming.
The opioid crisis has resulted in escalating rates of opioid use disorder in women of reproductive age and increased prevalence of fetal drug exposure. While medication for opioid use disorder (MOUD) - e.g., buprenorphine or methadone - improves maternal health outcomes, infants exposed to MOUD show a variety of physical and behavioral consequences. There are, however, few clinical or preclinical studies investigating long-term effects of MOUD exposure. The current work investigates the long-term effects of prenatal MOUD exposure on effort-based responding to a palatable food reward and gene expression in regions of the brain related to reward and feeding, including the nucleus accumbens and hypothalamus. Female Sprague Dawley rats were implanted with osmotic minipumps filled with methadone (10 mg/kg/day) or buprenorphine (1 mg/kg/day) or saline control (2.5 μL/hour for 28 days) and mated four days later. In adulthood, male and female offspring began sucrose pellet self-administration to assess the motivational strength of a food reward in MOUD-exposed animals compared to saline controls, followed by analysis of gene expression via RNAscope in situ hybridization. We observed long-term changes in reward motivation, where adults gestationally exposed to methadone - but not buprenorphine - demonstrated increased motivated responding for sucrose. We observed modest sex-dependent effects of MOUD on gene expression in the nucleus accumbens and arcuate nucleus of the hypothalamus following sucrose self-administration. These data suggest differential effects of methadone and buprenorphine on the brain and behavior, providing insight into the potential neuromolecular underpinnings of MOUD-induced changes in neural modulation of reward-motivated behavior.
Chronic neuroinflammation is recognized as a pivotal mechanism responsible for secondary damage following mild traumatic brain injury (mTBI), underscoring the critical need for therapeutic strategies capable of mitigating this pathological process. This study evaluated the anti-inflammatory properties of stearidonic acid ethanolamide (SDEA, C20H33NO2). The findings indicate that mTBI triggers persistent neuroinflammation, which is correlated with cognitive deficits. A ten-day treatment regimen with SDEA at 10 mg/kg/day facilitated the restoration of cognitive abilities and suppressed the neuroinflammatory cascade in a mouse model. Memory impairments and anxiety-like behaviors were quantified through behavioral testing. Immunohistochemical techniques were employed to examine alterations in Iba-1-positive microglia and nNOS-positive cells within the cortical and hippocampal regions (CA1 and DG). The expression profiles of pro- and anti-inflammatory markers (IL1β, IL6, TNFα, CD68, CD206) were analyzed via reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Furthermore, an in vitro model of LPS-induced inflammation in SIM-A9 microglial cells was utilized to investigate the impact of SDEA on the production of cytokines, reactive oxygen species (ROS), nitric oxide (NO), and nitrites. Integrative analysis of in vivo and in vitro data showed that SDEA: (1) improved behavioral deficits by reducing anxiety and improving working memory; (2) suppressed pro-inflammatory microglial activation and nNOS-positive cells; (3) lowered pro-inflammatory cytokine, ROS, NO, and nitrite concentrations; and (4) enhanced CD206 marker expression in the cerebral cortex. These collective findings underscore the therapeutic potential of SDEA for traumatic CNS injuries.
The brain undergoes profound molecular and structural changes during the aging process, resulting in the development of neurodegeneration, cognitive impairment, and increased vulnerability to chronic diseases. At the cellular level, brain aging is characterized by oxidative damage, genomic instability, and chronic low-grade inflammation known as inflammaging. Central to this process is Sirtuin 1 (SIRT1), a NAD+-dependent class III histone deacetylase, known for its regulatory role in chromatin remodeling, oxidative stress responses, mitochondrial biogenesis, and neuroplasticity. Recent research has identified SIRT1 as a molecular target capable of reversing or attenuating several hallmarks of aging, particularly within the central nervous system (CNS). This narrative review critically evaluates the emerging evidence surrounding the geroprotective effects of SIRT1 activators, which exert dual actions, senomorphic and senolytic, via modulation of signaling pathways, thereby reducing neuronal senescence, enhancing autophagy, and mitigating inflammatory responses. The discussion also addresses the region-specific role of SIRT1 across the brain, particularly in the hippocampus and hypothalamus, which are essential for memory, energy homeostasis, and resilience to stress. Additionally, this review explores how SIRT1 depletion during aging contributes to the development of synaptic dysfunction, impaired cognitive function, and susceptibility to neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The therapeutic potential of SIRT1 activators is supported by preclinical and early clinical studies, suggesting their value in preventing or delaying brain aging. Thus, SIRT1 could be a promising pharmacological target for age-associated brain disorders, warranting more robust translational studies to validate these findings in humans.
Neuroinflammation following spinal cord injury (SCI) is primarily driven by abnormal microglial activation and represents a major barrier to neurological recovery. This study aimed to investigate the regulatory role of leptin (LEP) in SCI, with a particular focus on its effects on the JAK-STAT signaling pathway, microglial polarization, and neuronal injury. Transcriptome sequencing of spinal cord tissues was performed to identify differentially expressed genes (DEGs), followed by enrichment, immune cell infiltration, and protein-protein interaction (PPI) analyses to determine key pathways involved in SCI. A mouse SCI model was established, and LEP expression was silenced using shRNA. Motor function recovery and pathological changes were assessed by Basso-Beattie-Bresnahan scoring, rotarod testing, Nissl staining, and hematoxylin-eosin staining. qRT-PCR, Western blot, and immunofluorescence were used to examine inflammatory mediators, microglial polarization markers, and JAK-STAT signaling. LPS-stimulated BV2 and primary microglia were used to evaluate the effects of LEP on inflammatory activation and polarization, and interferon gamma (IFN-γ) was applied to verify the involvement of JAK-STAT signaling. A microglia-PC12 co-culture system was used to determine the effects of LEP intervention on neuronal apoptosis and oxidative stress. Transcriptomic profiling revealed a marked enhancement of inflammation- and immunity-related pathways after SCI, with the JAK-STAT pathway identified as a major regulatory axis strongly associated with upregulated LEP expression. Functional analyses showed that LEP knockdown significantly improved motor recovery after SCI. LEP silencing suppressed the phosphorylation of JAK2 and STAT3, promoted the shift of microglia from the M1 to the M2 phenotype, reduced iNOS, TNF-α, and IL-6, and increased IL-4 and IL-10 expression. IFN-γ partially reversed these effects, confirming that LEP regulates microglial polarization through the JAK-STAT pathway. LEP knockdown in microglia also attenuated neuronal apoptosis and oxidative stress, decreasing cleaved caspase-3, Bax, MDA, and ROS levels while restoring Bcl-2 and enhancing SOD activity. LEP may function as a modulator associated with JAK-STAT signaling activation during neuroinflammation after SCI. Integrating transcriptomic and mechanistic evidence, we demonstrate that LEP silencing is associated with suppressed activation of JAK-STAT pathway, promotes M2 microglial polarization, reduces neuronal apoptosis and oxidative damage, and ultimately enhances spinal cord repair and functional recovery.
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Juvenile myoclonic epilepsy (JME) is one of the most common idiopathic generalized epilepsy syndromes, yet its molecular pathogenesis remains incompletely understood. Circular RNAs (circRNAs) are stable non-coding RNAs with important regulatory roles and increasing relevance in neurological disorders. In this study, we investigated for the first time the association between selected circRNAs (hsa_circ_0000218, hsa_circ_0000229, hsa_circ_0000249, hsa_circ_0002010, and hsa_circ_0000143) and JME. Total RNA was isolated from peripheral blood samples of 41 patients with JME and 41 healthy controls, followed by RNase R treatment and quantitative real-time PCR analysis. Expression levels of hsa_circ_0002010 and hsa_circ_0000143 were significantly upregulated in patients with JME compared with controls (both p < 0.001), whereas hsa_circ_0000249 was significantly downregulated (p < 0.001). No significant differences were observed for hsa_circ_0000218 or hsa_circ_0000229. Sex-specific analyses revealed differential expression patterns, and hsa_circ_0002010 and hsa_circ_0000249 were associated with drug resistance. Our findings suggest that certain circRNAs may be involved in molecular pathways related to JME and may provide preliminary information to inform future studies exploring their potential relevance in JME.
Neurodegenerative diseases impose a substantial and growing global burden, affecting millions worldwide and leading to high medical, social, and economic costs. These are characterized by progressive neuronal dysfunction and loss, leading to cognitive, motor, and behavioral impairments. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease are driven by intertwined mechanisms of oxidative stress, neuroinflammation, protein aggregation, and neuronal apoptosis. Activation of the TLR-2/NF-κB axis promotes neuroinflammation and pyroptotic cell death through excessive production of pro-inflammatory cytokines, contributing to neuronal damage. Dysregulation of the TLR-2/Akt/mTOR pathway impairs autophagy, leading to defective clearance and accumulation of α-synuclein, a central event in synucleinopathies. Moreover, compromised Nrf2-mediated antioxidant signaling weakens cellular redox homeostasis and anti-apoptotic defenses, thereby linking redox imbalance to caspase-dependent neuronal apoptosis. Given the complex and multifactorial nature of neurodegenerative diseases, there is a pressing need for multitarget agents. Phloretin is a natural dihydrochalcone predominantly found in apples, pears, and strawberries. It exhibits broad pharmacological activities, including antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective effects, making it a promising multitarget phytochemical for neurodegenerative conditions. Phloretin mediates its neuroprotective properties through the modulation of several mediators, including Aβ, TLR-2, NF-κB, COX, iNOS, PPARγ, Nrf2, beclin-1, Bax, Bcl-2, caspases, PI3K/Akt, mTOR, pro-inflammatory cytokines, and antioxidant enzymes, among others. Despite compelling preclinical evidence, critical gaps remain regarding phloretin's effects on inflammasome initiation, ER stress responses, mitophagy, neurotrophic signaling, and, importantly, its clinical safety and efficacy, underscoring the need for integrated mechanistic studies and well-designed clinical trials.
Traumatic spinal cord injury (SCI) shows pronounced biological sex differences in incidence and short-term outcomes, yet mechanistic studies and therapeutic development are not consistently sex-informed. Here we summarize evidence that sex hormones, sex-chromosome effects and immune-glial interactions shape key components of the secondary injury cascade, including blood-spinal cord barrier (BSCB) disruption, neuroinflammation, oxidative stress, cell death and remyelination. Estrogens and progesterone generally support barrier stabilization, temper leukocyte infiltration, bias microglia/macrophages toward reparative programs, and promote neurotrophin signaling and myelin repair. In males, post-injury androgen deficiency together with stronger early innate immune activation may exacerbate oxidative damage, demyelination and scar formation, potentially limiting plasticity. Clinical evidence remains limited and confounded, but available data support the need for adequately powered, sex-stratified trials, particularly for time-sensitive hormonal and immunomodulatory interventions. Incorporating sex as a biological variable in experimental design and translation may improve target selection, dosing and therapeutic windows for SCI.
Down syndrome (DS), or trisomy 21 (T21), represents the most common genetic cause of intellectual disability worldwide and is associated with a wide range of medical, developmental, and neurodegenerative conditions, including a universal predisposition to early-onset Alzheimer's disease (AD). Since its establishment in 2014, the Trisomy 21 Research Society (T21RS) has provided a global forum for advancing DS research across disciplines and promoting translational efforts to improve health and quality of life. Every two years, T21RS hosts an international scientific meeting that brings together researchers, clinicians, self-advocates, families, and industry stakeholders. In 2024, the 5th T21RS International Conference was held in Rome, Italy, from June 5 to 8, under the theme "Promoting Research Excellence in Down Syndrome." The meeting brought together about 500 scientists from 26 countries across five continents, and more than 900 attendees overall, including families and caregivers. The scientific program featured 5 keynote lectures, 2 satellite meetings, 17 symposia, 7 nano symposia, 2 workshops, and 1 industry-focused session, totaling more than 150 oral presentations. More than 230 abstracts were presented as posters. The conference covered research across the lifespan of individuals with DS, spanning genomic and epigenetic regulation, molecular and cellular mechanisms, preclinical and experimental models, cognition and behavior, neurodevelopment, aging and neurodegeneration, co-occurring medical conditions, and therapeutic interventions. Dedicated sessions focused on capacity-building in DS research and societal engagement were established. Significantly, T21RS promoted inclusivity by supporting 60 young investigator fellowships, providing childcare awards, and organizing a two-day program for families and caregivers in collaboration with Italian DS associations. This proceeding summarizes the main scientific highlights of the 5th T21RS International Conference, reflecting the latest advances in DS biology, clinical research, biomarker development, and therapeutic innovation.
Emerging evidence indicates that circular RNAs (circRNAs) can encode functional peptides, which participate in the regulation of both physiological and pathological processes. CircRNA-derived peptides are involved in the regulation of various cellular functions and signaling pathways by interacting with specific biological molecules. These peptides can influence tumor progression by modulating key signaling pathways and by promoting or inhibiting malignant phenotypes through defined mechanisms. Consequently, the suppression of particular circRNA-encoded peptides may contribute to the inhibition of glioma progression or facilitate tumor elimination. Given that the expression of certain circRNAs is elevated in glioma tissues and associated cells, they hold potential as diagnostic biomarkers and therapeutic targets. This review provides a comprehensive overview of circRNA-encoded peptides, focusing on their regulatory roles and functional mechanisms in glioma. We discuss how these small peptides contribute to glioma pathophysiology and consider their prospective applications in diagnosis, prognosis, and targeted therapy.
Brain energetics rely on a distributed partnership among cell types and fuel sources. Beyond astrocytic glycogen, the brain has limited conventional energy reserves. Emerging evidence broadens this view by positioning myelin and oligodendrocytes as active stabilizers of metabolic homeostasis. They align substrate delivery with demand and directly sustain axonal ATP production. This review highlights current understanding that myelin lipid stores function as a conditional metabolic buffer that can be mobilized when glycolytic supply wanes. Firstly, we outline the protective repertoire of myelin (e.g., adaptive myelination, antioxidant defense, and metabolic coupling) and then summarize myelin lipid metabolism, spanning de novo synthesis and β-oxidation. We next demonstrate disease contexts marked by energetic failure. Specifically, Alzheimer’s disease exhibits a chronic metabolic downshift, whereas ischemic stroke produces an acute collapse of energy production. Both states may recruit the proposed buffer. However, leveraging lipid-derived fuels is not without risk. Reactive oxygen species, acidosis, and iron handling must be tightly regulated to avoid collateral injury. Finally, we highlight methodological priorities that can resolve mechanism in vivo, including white matter-resolved fluxomics, myelin specific imaging paired with proteo-lipidomics, and lineage-restricted perturbations of β-oxidation and autophagy. On the translational front, we propose stage specific strategies. In summary, defining when and how to mobilize and supplement myelin lipid reserves could transform a conceptual buffer into a practical lever for disease modification in hypometabolic brain disorders.
Riboflavin responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD) is an inherited metabolic disorder which is good responsive to riboflavin treatment. The phenotypic spectrum of adult-onset RR-MADD is highly heterogeneous. In this study, we described three patients with adult-onset RR-MADD presented with muscle weakness and spinal cord involvement. These three patients presented with adult-onset limb weakness, dyspnea, along with sensory levels changes (patient 1 below T2 level, patient 2 below T6 level, and patient 3 below T12 level, respectively). All patients displayed elevated acylcarnitine and urinary organic acids. Muscle biopsies in patient 1 and patient 2 revealed the presence of lipid vacuoles and COX-negative fibers. Genetic analysis identified ETFDH mutation (c.524G > A (p.R175H)) in patient 1, and a compound heterozygous ETFDH mutation (c.34G > C (p.A12P)/c.736G > A (p.E246K)) in patient 2. Spinal-cord MRI excluded structural lesions, whereas muscle MRI indicated fatty infiltration. Short-term riboflavin treatment proved effective in alleviating muscle weakness, while long-term administration of riboflavin, coenzyme Q10, and vitamin B12 demonstrated efficacy in alleviating spinal cord involvement. Inconclusion, our findings suggest that spinal cord involvement may manifest in certain patients with adult-onset RR-MADD, which expand the neurological spectrum of adult-onset RR-MADD.
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In Alzheimer's disease (AD), senescent astrocytes fuel neuroinflammation and neuronal damage via the senescence-associated secretory phenotype (SASP). Calcium signaling plays a crucial role in this process, but the underlying molecular mechanisms remain elusive. We retrieved scRNA-seq data from the Gene Expression Omnibus (GEO) for AD and control brains. After cell-type annotation, we resolved astrocyte sub-clusters. Pseudotime trajectory and differential-expression analyses identified SORBS1 as a key senescence-related gene, which we followed with gene-set enrichment analysis. Next, we established an in vitro AD model by treating astrocytes with amyloid-β (Aβ). We evaluated astrocyte senescence using SA-β-gal staining, qRT-PCR, Western blot (WB) for senescence markers, and ELISA for SASP cytokines. We measured concentration of Ca2+ with Fluo-4 AM probes. Subsequently, bioinformatic screening predicted FBXO22 as an interactor of SORBS1 and BAG3 as a ubiquitination substrate of FBXO22. We validated these interactions using Co-IP and in vitro ubiquitination assays. Finally, we constructed an astrocyte-neuron co-culture model. We detected neuronal cell viability, AChE activity, AD phenotype-related protein expression, apoptosis, and levels of inflammatory factors using MTT assay, specific kits, WB, flow cytometry, and ELISA, respectively, to assess neuronal damage. ScRNA-seq analysis revealed a marked reduction in astrocyte expression in AD brains, which may result from cellular senescence. The SASP gene SORBS1 was selectively up-regulated in astrocytes and significantly enriched in calcium-signaling pathways. Functional assays confirmed that SORBS1 accelerated astrocyte senescence. Mechanistically, SORBS1 interacted with FBXO22 to promote the ubiquitin-dependent degradation of BAG3, thereby amplifying calcium signaling, accelerating astrocyte senescence, and contributing to AD-related neuronal damage. We uncover a novel mechanism by which the SORBS1/FBXO22/BAG3 axis drives astrocyte senescence through the regulation of calcium signaling, thereby influencing AD-related neuronal damage. This finding provides a potential therapeutic target for AD treatment by targeting astrocyte senescence.
The cerebral adenosinergic system is involved in sleep-wake regulation and presumably represents a neuro-molecular correlate of homeostatic sleep pressure. For acute sleep deprivation, it has been shown that increased cerebral A1 adenosine receptor (A1AR) availability was related to impairments in cognitive performance. The present study examined A1AR availability in response to chronic sleep restriction and recovery. To quantify A1AR availability we used 8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F] CPFPX) positron emission tomography in 21 volunteers after 5 nights with 5-h sleep opportunities followed by 8 h recovery sleep. Data were compared to a control group of 15 volunteers who slept 8 h each night. In addition, polysomnography, cognitive performance, and alertness were recorded. Chronic sleep restriction did not increase the A1AR availability. Slow wave sleep (SWS) and EEG slow-wave-activity (SWA) in the first 5 h of sleep did not differ from baseline (BL), but SWA in the last 3 h of sleep was increased and cognitive performance and alertness were impaired. While SWA returned to BL in the last 3 h of recovery sleep, performance, and alertness remained impaired. The results indicate that chronic sleep loss likely induces parallel upregulations of extracellular adenosine and A1AR resulting in no net gain in receptor availability. The results contrast with findings from acute sleep deprivation in which we found impaired performance and increased A1AR availability that were restored to rested levels after recovery sleep. The findings reveal fundamental differences in the mechanisms through which acute and chronic sleep loss affect adenosinergic regulation and cognitive performance.
Scrub typhus, caused by the obligate intracellular bacterium Orientia tsutsugamushi(O. tsutsugamushi), is an acute febrile illness. While neurological complications are known, hearing loss is an uncommon manifestation, and coinfection with Epstein-Barr virus(EBV) presents unique diagnostic and pathophysiological challenges. A 58-year-old woman presented with a 5-day history of high fever, severe headache, and constitutional symptoms. She reported transient, fluctuating bilateral hearing loss. Examination revealed characteristic eschars on her legs. Laboratory findings indicated hepatic impairment and systemic inflammation. Metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid detected O. tsutsugamushi and EBV. EBV serology profile (VCA-IgG+, VCA-IgM-, EBNA-IgG+) suggested viral reactivation. The patient failed to respond to initial beta-lactam antibiotic therapy but showed rapid and complete resolution of symptoms, including hearing loss, after initiation of doxycycline. At the 1-month and 3-month follow-up, audiological assessment confirmed normal hearing. This case highlights a rare presentation of scrub typhus with EBV coinfection involving fluctuating hearing loss. The dramatic response to doxycycline suggests this auditory symptom may be a reversible, immune-mediated complication of O. tsutsugamushi infection. Physicians should be aware of this potential manifestation in endemic areas. The immunological interplay between these pathogens warrants further investigation.
The inflammatory response is essential for host defense, but its persistence can lead to chronic systemic inflammation (CSI). Soluble urokinase-type plasminogen activator receptor (suPAR) has emerged as a reliable biomarker of CSI because elevated levels consistently indicate the presence and progression of chronic disease as well as increased mortality risk. There is growing evidence that CSI influences neurovascular regulation, including changes in blood-brain barrier (BBB) integrity, which suggests that suPAR may also be relevant to central nervous system (CNS) processes. This narrative review summarizes current findings on suPAR in CSI and examines its emerging implications for CNS. Higher suPAR concentrations have been linked to working memory impairment, executive dysfunction and worse clinical outcomes after brain injury. Evidence also indicates that suPAR reflects neuroinflammatory activity and BBB disruption, especially in conditions marked by heightened immune activation. However, available studies differ widely in design, sample type, follow-up duration and population characteristics, which limits mechanistic interpretation. Although suPAR appears to be a promising biomarker connecting systemic inflammation to CNS dysfunction, its role within the brain remains unclear. Future studies should determine its cellular origin, clarify its involvement in inflammatory signaling pathways and establish its predictive and prognostic value.
Myelin, essential for rapid nerve conduction and axonal integrity in the central and peripheral nervous systems, is compromised in demyelinating diseases, leading to neurological deficits and progressive neurodegeneration. Although remyelination can occur, regeneration in adults is often limited, resulting in incomplete repair and impaired nerve function. In multiple sclerosis (MS), an immune-mediated demyelinating disease with diverse clinical phenotypes, progression and disability correlate with demyelination and failed remyelination, influenced by genetic and environmental factors. A well-established method to study MS-like demyelination and its cellular and molecular mechanisms utilizes cuprizone (CPZ), extensively studied in adult rodents. Although early-onset demyelination often causes lifelong disability, its pathophysiology remains poorly understood, underscoring the need for models to dissect its biological features. Here, we characterized the effects of early-age CPZ-induced demyelination in juvenile naïve mice, focusing on region-specific vulnerability and neuroinflammatory responses. One-month-old mice were exposed to 0.2% CPZ for five weeks, followed by behavioral, cellular, and transcriptomic analyses. Susceptibility to the early-exposure of CPZ varied between the analysed brain regions. The midline corpus callosum and motor cortex were highly vulnerable, showing marked reductions in myelin together with elevated microglial activation. Other regions, including the hippocampus and amygdala, showed milder susceptibility, often restricted to changes in Mbp or Iba1 transcript levels without corresponding alterations in oligodendrocyte or microglial cell numbers. Behaviorally, early CPZ exposure reduced locomotor activity but did not produce robust anxiety-like or cognitive deficits. Together, these findings reveal distinct regional patterns of early-onset demyelination and neuroinflammation and support CPZ exposure in juvenile mice as a relevant model for multifocal juvenile demyelination, including paediatric-onset MS, and its impact on neurodevelopment. The online version contains supplementary material available at 10.1007/s12017-026-08911-2.