Exp. Neurol. [JOURNAL]
Sun
200 papers
Opportunities and challenges for the application of single-cell RNA sequencing and spatial transcriptomics in ischemic stroke.
Wang Z, Hao Z, Xu S … +6 more , Wu H, Wu J, Zhao M, Wang R, Xing L, Wang J
Exp Neurol · 2026 Jul · PMID 42402308 · Publisher ↗
Ischemic stroke (IS) is characterized by high rates of morbidity, disability and mortality. The pathological process underlying IS involves spatiotemporal dynamic responses of multiple cell types and marked cellular hete...
Ischemic stroke (IS) is characterized by high rates of morbidity, disability and mortality. The pathological process underlying IS involves spatiotemporal dynamic responses of multiple cell types and marked cellular heterogeneity which cannot be fully elucidated using traditional bulk sequencing technologies. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have provided high-resolution tools for investigating pathological mechanisms and developing precise diagnostic and therapeutic strategies for IS. In this review, we systematically summarize the core principles, mainstream platform characteristics and applicability of these two technologies in IS research, focusing particularly on how they have helped to reveal dynamic cellular evolution following ischemia, spatial molecular heterogeneity between the infarct core and penumbra, and key differences between human and mouse models. We also review key breakthroughs, including the LGALS9-CD44 repair signaling axis, the optimization of oligodendrocyte precursor cell (OPC) transplantation, and the molecular classification of IS. In addition, we discuss the potential for this technology to be translated clinically, and analyze the levels of accompanying evidence for relevant research findings from four dimensions: the screening of early diagnostic biomarkers, the development of novel therapeutic targets, improving molecular understanding for cell therapy, and the construction of disease classifications at the molecular level. We also highlight potential core challenges including the low capture efficiency of brain cells, inherent contradiction between spatial resolution and sensitivity, scarcity and insufficient standardization of human samples, and prominent obstacles in translating preclinical results to clinical practice. In future, the optimization of technologies that are specific to brain tissue, the construction of multicenter large-sample human stroke databases, and the implementation of cross-species validation studies, will help to promote the application of scRNA-seq and ST from basic mechanistic analysis to precise clinical application in the field of IS, thereby providing scientific support for improving the diagnosis and treatment of IS.
Behavioral and functional characterization of early-stage Parkinson's disease models reveals attentional deficits and circuit-level connectivity alterations.
Naïdji C, Devos D, Betrouni N … +1 more , Laloux C
Exp Neurol · 2026 Jul · PMID 42401254 · Publisher ↗
Parkinson's disease (PD) is preceded by a prolonged prodromal phase during which subtle cognitive and behavioral alterations emerge before overt motor symptoms. Experimental models reproducing these early stages are esse...
Parkinson's disease (PD) is preceded by a prolonged prodromal phase during which subtle cognitive and behavioral alterations emerge before overt motor symptoms. Experimental models reproducing these early stages are essential for understanding disease mechanisms and identifying early biomarkers. In this study, we performed the multimodal characterization of two toxin-based rat models of prodromal PD induced by bilateral nigral injections of 6-hydroxydopamine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Animals were assessed over 2 months using behavioral testing, functional magnetic resonance imaging (fMRI), and histologic analyses. Both models produced moderate, heterogeneous dopaminergic degeneration within the nigrostriatal pathway, consistent with prodromal stages. Motor impairments remained limited whereas robust attentional deficits were detected. fMRI revealed region-specific connectivity alterations aligned with behavioral impairments, suggesting early circuit-level dysfunction despite the absence of widespread network disruption. To address inter-individual variability, a clinically inspired staging framework was implemented based on dopaminergic lesion severity, attentional performance, and sensorimotor impairment. This phenotype-based classification stratified animals into sham, asymptomatic, early, and advanced stages independent of the toxin used. Together, these findings demonstrate that moderate bilateral dopaminergic degeneration produces early cognitive and circuit-level alterations, and highlight the value of multimodal phenotyping for studying prodromal PD and identifying early functional biomarkers.
Neuropathological and functional impact of astrocyte-derived extracellular vesicles in an aged model of Alzheimer's disease.
Quach B, Salehi S, Roufegarinejad R … +5 more , Guleria VS, Mante M, Florio J, Rissman RA, Winston CN
Exp Neurol · 2026 Jul · PMID 42398567 · Publisher ↗
Extracellular vesicles (EVs) are lipid-bound particles that transfer cargos between cells. While plasma neuronal-derived EVs (NEVs) from individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) have...
Extracellular vesicles (EVs) are lipid-bound particles that transfer cargos between cells. While plasma neuronal-derived EVs (NEVs) from individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) have been reported to exhibit high pathogenic potential, this study examined the impact of astrocyte-derived EVs (AEVs) in an aged AD mouse model. Plasma AEVs were isolated from cognitively normal control (CNC), MCI, and AD individuals using GLAST-based immunocapture and AEV size, purity, and tetraspanin were validated by flow cytometry, nanoparticle tracking, and super-resolution microscopy. AEVs pooled by clinical cohort were injected into the hippocampus of 6-month-old female PSAPP mice. Behavioral, biochemical, and neuropathological outcomes were assessed 6 months later. Rotarod assessment revealed significant impairment in motor coordination (p < 0.0001) in mice receiving MCI- and AD-AEVs compared with those receiving CNC-AEVs. While Morris water maze (MWM) also demonstrated that CNC-AEVs injected mice exhibited a trend toward increased target quadrant entries and faster escape latencies, these measures did not reach did not reach statistical significance. No overt changes were observed in the staining of amyloid plaque burden (6E10), and astrogliosis (GFAP). Immunoblotting of 82E1 and 22C11 confirmed Aβ/AAP levels remained similar across all injected mice, whereas increased cortical tau accumulation was observed in MCI- and AD-AEV injected mice. Cerebellar synaptic density (SY-38) remained unchanged. These findings suggest that while human-derived AEVs can precipitate early tau-related changes and motor coordination deficits, they do not significantly alter overall amyloidosis or astrocyte-reactivity at this time point. Further investigation is required to determine the viability of AEVs as biomarkers or therapeutic targets given the subtle nature of the observed structural pathology.
PI3K/Akt pathway in ischemic stroke: A central regulator of neuronal survival and repair.
Mariya, Khan MM, Badruddeen … +1 more , Ahmad U
Exp Neurol · 2026 Jul · PMID 42386156 · Publisher ↗
Stroke is a leading cause of death and disability in the world, and the majority of ischemic strokes are caused by cerebral ischemia. Neurons are deprived of oxygen and nutrients when blood flow to the brain is disrupted...
Stroke is a leading cause of death and disability in the world, and the majority of ischemic strokes are caused by cerebral ischemia. Neurons are deprived of oxygen and nutrients when blood flow to the brain is disrupted, which initiates cascades of events that includes inflammation, oxidative stress, excitotoxicity, and ultimately cell death. However, cells also trigger defense signaling networks that impact neuronal survival. On activation of receptor tyrosine kinases (RTKs) by growth factors such as insulin-like growth factor-1 (IGF-1), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF), pro-survival reactions are initiated through the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, which modulates many downstream effectors, including mammalian target of rapamycin (mTOR), glycogen synthase kinase-3 beta (GSK-3β), nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB), and forkhead box O (FOXO). These molecules collectively modulate apoptosis, stimulate neurogenesis, control autophagy, and lessen oxidative stress. Due to its various functions, the PI3K/Akt pathway is a feasible therapeutic target for treating ischemic brain injury. This review summarises an overview of our current knowledge of PI3K/Akt signaling in cerebral ischemia, including its upstream triggers and downstream mediators. We also discuss about how altering this system may lead to novel approaches to stroke recovery and neuroprotection. We emphasize focusing on PI3K/Akt pathway that might be essential for creating potent therapies for stroke and its long-term neurological effects.
Hepatokines and stellakines in liver and neurological diseases: The liver-brain axis.
Park J, Guo F, Lee JE … +1 more , Cheon SY
Exp Neurol · 2026 Jul · PMID 42386155 · Publisher ↗
Interorgan communication is essential for maintaining homeostasis. Numerous mediators, including cytokines and adipokines, have been identified, and their roles in interorgan crosstalk have been clarified. In particular,...
Interorgan communication is essential for maintaining homeostasis. Numerous mediators, including cytokines and adipokines, have been identified, and their roles in interorgan crosstalk have been clarified. In particular, interactions between peripheral organs and the central nervous system (CNS), such as the liver-brain axis, have become a major focus for identifying therapeutic targets for disease. Among the various secreted mediating factors, such as hepatokines and stellakines, are released from hepatocytes and hepatic stellate cells, respectively in response to diverse stimuli, and they contribute to hepatic inflammation, fibrosis, and tissue injury and repair. Under pathological conditions, such as metabolic dysfunction-associated steatotic liver disease (MASLD), aberrantly expressed hepatokines and stellakines can enter the bloodstream and the brain parenchyma via disrupted blood-brain barrier (BBB). These factors can lead to BBB impairment or recovery, modulate peripheral immune cell infiltration, and either exacerbate or attenuate neuroinflammation, thereby influencing the development and suppression of neurological diseases. They may also aggravate or alleviate neuropsychiatric symptoms. Accordingly, therapeutic modulation of hepatokines or stellakines can have either detrimental or beneficial effects within the neural microenvironment. Collectively, although research on their roles in the liver-brain axis remains limited, elucidating their mechanisms of action may help identify novel preventive and therapeutic targets for neurological diseases.
Structural dynamics of α-Synuclein: Multi-scale imaging insights into pathological progression across Synucleinopathies.
Yang H, Tian Z, Liu J
Exp Neurol · 2026 Jun · PMID 42379257 · Publisher ↗
The misfolding and aberrant aggregation of alpha-synuclein (α-syn) constitute the central pathological hallmark of a spectrum of synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple s...
The misfolding and aberrant aggregation of alpha-synuclein (α-syn) constitute the central pathological hallmark of a spectrum of synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. A continuous ultrastructural conformational evolution from disordered monomers through toxic oligomers to amyloid fibrils is linked to the formation of Lewy pathology and the progressive functional decline of neurons. This review integrates structural dynamics revealed by multi-scale electron microscopy (EM) techniques-including transmission electron microscopy, immunoelectron microscopy, cryo-electron microscopy (cryo-EM)/cryo-electron tomography, correlative light and electron microscopy, and volume electron microscopy-to systematically delineate the polymorphic spectrum of α-syn assemblies during pathogenesis. This spectrum spans liquid-liquid phase separation-associated condensate precursors and membrane-active toxic intermediates to stable fibrillar and inclusion structures. High-resolution cryo-EM studies have identified disease-specific "structural strains" across synucleinopathies, indicating that genetic variations, disease context, and microenvironmental factors collectively shape distinct atomic conformations that likely correlate with differential toxicity, propagation potential, and clinical phenotypes. EM evidence at the cellular level further elucidates the morphological associations between α-syn aggregates and disruption of synaptic vesicle homeostasis, mitochondrial structural damage, and impairment of the lysosomal-autophagic pathway. Contextualizing these findings within the spatiotemporal progression pattern outlined by the Braak staging system, this article examines the evolution of dominant structural morphologies across disease stages and their pathological significance. It also looks ahead to how in situ three-dimensional imaging technologies are driving a paradigm shift from analyzing "static in vitro structures" to deciphering "dynamic intracellular networks." Finally, the review identifies the core challenge: establishing a verifiable mapping between in vitro-resolved structures and in situ pathological states, and linking structural classifications to specific molecular mechanisms and phenotypic endpoints. This endeavor is crucial for providing a theoretical foundation for developing precise intervention strategies targeting specific pathogenic conformations or propagation nodes.
Retraction notice to 'Mitochondrial ferritin upregulation reduced oxidative stress and blood-brain-barrier disruption by maintaining cellular iron homeostasis in a neonatal rat model of germinal matrix hemorrhage' [Experimental Neurology 374 (2024) 114703].
Yuan Y, He Q, Yang X … +16 more , Flores JJ, Huang L, Luo X, Zhang X, Zhang Z, Li R, Gu L, Dong S, Zhu S, Yi K, Han M, Wu L, Zhou Y, Zhang JH, Xie Z, Tang J
Exp Neurol · 2026 Jun · PMID 42366134 · Publisher ↗
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Sivelestat sodium alleviates blood-brain barrier dysfunction after traumatic brain injury by reduction of NETs formation.
Yang C, Sang X, Hong X … +11 more , Hou X, Chen W, Qu X, Li C, Shi H, Peng C, Guo Y, Ye Y, Zhao Q, Zhang D, Hou L
Exp Neurol · 2026 Jun · PMID 42364708 · Publisher ↗
BACKGROUND: Brain endothelial cells (bECs) dysfunction plays a key role in blood-brain barrier (BBB) disruption after traumatic brain injury (TBI), contributing to a vicious cycle that worsens disease progression. Althou...
BACKGROUND: Brain endothelial cells (bECs) dysfunction plays a key role in blood-brain barrier (BBB) disruption after traumatic brain injury (TBI), contributing to a vicious cycle that worsens disease progression. Although neutrophil extracellular traps (NETs) are known to impair the BBB, their mechanisms in TBI remain unclear. Sivelestat sodium, an inhibitor of neutrophil elastase (NE) required for NETs formation, may offer a therapeutic strategy for TBI. METHODS: A controlled cortical impact (CCI) model was used to induce TBI in mice. NETs involvement was confirmed by immunofluorescence and Western blot, and the effect of sivelestat sodium on NETs formation in the peri-injury region was assessed. Transcriptome sequencing explored molecular mechanisms post-treatment. BBB integrity and vascular endothelial pyroptosis were evaluated via Western blot, immunofluorescence, and Evans blue extravasation. RESULTS: NETs expression in the peri-injury area peaked at 72 h after TBI and was reduced by sivelestat sodium treatment, which also improved neurological function in behavioral tests. Transcriptome sequencing unveiled sivelestat sodium may contribute to post-TBI recovery via neuroinflammatory and pyroptosis pathways. Furthermore, Western blot and immunofluorescence analyses demonstrated that sivelestat sodium treatment in TBI mice resulted in decreased expression of GSDMD-N and cleaved caspase-1 proteins, increased expression of tight junction proteins such as ZO-1, and reduced Evans blue extravasation. CONCLUSIONS: This study suggests that sivelestat sodium protects the BBB and mitigates TBI-related injury by suppressing NETs formation and subsequent vascular endothelial pyroptosis, highlighting its therapeutic potential.
Corrigendum to "Primary and Immortalized Microglia Exhibit Divergent Responses to Hemoglobin" [Experimental Neurology 403 (2026) 115838].
Umpornpun KP, Oldham BB, Vekaria HJ … +6 more , Zamorano M, Merchant M, Johnson G, Wang GY, Eskandari R, Miller BA
Exp Neurol · 2026 Jun · PMID 42362427 · Publisher ↗
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Persistent deficits in the motor unit following mono and dual administration of SMN up-regulators in the SmnΔ7 mouse model of spinal muscular atrophy.
Partlova I, Comley LH, Haigh AE … +2 more , Tarodo PS, Murray LM
Exp Neurol · 2026 Jun · PMID 42362038 · Publisher ↗
Spinal muscular atrophy (SMA) is characterized by motor neuron loss and neuromuscular junction (NMJ) pathology. Although SMN-upregulating therapies such as Nusinersen markedly improve survival and motor function for many...
Spinal muscular atrophy (SMA) is characterized by motor neuron loss and neuromuscular junction (NMJ) pathology. Although SMN-upregulating therapies such as Nusinersen markedly improve survival and motor function for many patients, impactful deficits often remain. In order to generate the next generation of therapy for SMA, it is critical that we understand the cellular basis for persistent deficits and find strategies to support and promote motor unit repair. Here we performed a detailed temporal analysis of the distal motor unit following administration of the Smn up-regulator Nusinersen in a range of differentially vulnerable cranial muscles in the SmnΔ7 mouse model. We show that early administration of Nusinersen facilitates progressive recovery of motor endplate innervation, even in the most vulnerable muscles. However, there is a persistent decrease in intramuscular motor axon number and increase in motor unit size, which is most severe in the most vulnerable muscles. We further show that combining Nusinersen with the Risdiplam tool compound SMN-C8 leads to a synergistic increase in Smn levels but does not produce broad improvements in motor unit recovery beyond those achieved with Nusinersen alone. Nevertheless, dual therapy resulted in significant improvement in hindlimb splay score from post-natal day 10 onwards. These effects suggest that enhanced SMN restoration may confer selective functional and structural benefits, although these were insufficient to fully rescue persistent motor unit pathology. Collectively, our findings demonstrate that early Smn restoration enables robust NMJ reinnervation but fails to prevent axon loss and motor unit remodelling. The limited additional benefit observed with dual SMN up-regulation, despite synergistic increases in Smn levels, suggests a potential ceiling effect for SMN-dependent rescue and highlights the need for adjunctive SMN-independent strategies aimed at preserving axons, stabilizing motor units, and promoting neuromuscular regeneration in SMA.
Roles of astrocytic Connexin 43 gap junctional deficit in alpha-synucleinopathy and inflammation relevant to Parkinson's.
Hastings N, Rahman S, Kuan WL … +15 more , Alfaidi M, Fox S, Erkamp NA, Andrzejewska E, Whitehead M, Zakirov A, Unwin RD, Baranes K, Schmidt R, Oliinyk A, Aref D, Brotchie J, Knowles TPJ, Malliaras GG, Kotter MRN
Exp Neurol · 2026 Jun · PMID 42362037 · Publisher ↗
Parkinson's disease (PD) is a neurological condition with the fastest rise in prevalence globally; it affects over 10 million people and is currently incurable. Originally considered purely a disorder of the dopaminergic...
Parkinson's disease (PD) is a neurological condition with the fastest rise in prevalence globally; it affects over 10 million people and is currently incurable. Originally considered purely a disorder of the dopaminergic nigrostriatal pathway, PD is increasingly recognized as a complex pathology affecting different cell types and multiple brain regions beyond substantia nigra of midbrain. These findings call for new conceptual approaches to translational research in PD which would aim to restore functions of multiple cell types. We previously demonstrated a decrease in astrocytic connexin43 (Cx43) protein in human late-stage idiopathic PD, but its functional consequences remain unknown. In the present work we hypothesized that the key etiologies relevant to human idiopathic PD include inflammation and α-synuclein aggregation, which were applied to a number of model systems ranging from rat and human cultured astrocytes, co-cultures, and rat models of PD. We report that these challenges structurally and functionally disrupt astrocytic networks comprised of Cx43-containing gap junctions (GJs) in astrocytes from multiple brain regions and across species (rat, human), and that Cx43 is downregulated in α-synuclein pre-formed fibril-induced rat PD models. Causal rather than correlational roles of Cx43 dysfunction in PD pathology are suggested as experimental downregulation of Cx43 with shRNA dysregulates calcium signaling and exacerbates α-synuclein aggregation, while pharmacological preservation of GJs (and possible hemichannel closure) using a Cx43-modulating compounds danegaptide (GAP-134, ZP1609) reduces aspects of pathology induced by inflammation and α-synuclein in vitro and in vivo. Cx43 may therefore represent a new therapeutic target for disease modification in PD.
Apelin-driven metabolic ratios reflect post-stroke recovery in mice.
Petrault M, Gele P, Berezowski V … +4 more , Devos D, Ouk T, Petrault O, Bastide M
Exp Neurol · 2026 Jun · PMID 42341898 · Publisher ↗
Visceral fat gain and the progressive onset of metabolic disorders precipitate stroke risk and prompt the middle-aged population to cognitive decline. Preclinical research has recently focused on total apelin, a neuropro...
Visceral fat gain and the progressive onset of metabolic disorders precipitate stroke risk and prompt the middle-aged population to cognitive decline. Preclinical research has recently focused on total apelin, a neuroprotective peptide whose cerebral action after release in plasma by adipose tissue remains elusive. The ratio between plasma apelin and lipids is suspected to influence prognosis in patients with cardiovascular diseases. This study challenged ratios of plasma apelin to cholesterol or glucose in reflecting post-stroke recovery of mature adult mice after a 6-month high-fat diet (HFD). Mice under HFD developed overweight (+10%, p < 0.001), hyperglycemia (21%, p < 0.001) and hypercholesterolemia (+68%, p < 0.001). Plasma apelin decreased with age in all mice (F = 35.94, p < 0.001), but a 30-min middle cerebral artery occlusion (MCAO) induced a 27% drop in plasma apelin (p < 0.01) in HFD-fed mice only, as well as a higher acute mortality (29%) than in normal diet (ND)-fed mice (19%). Ten days after MCAO, apelin levels normalized in HFD-fed mice, but were still decreasing in ND-fed mice (p < 0.01). However, high pre-stroke ratios revealed an upregulation of brain apelin receptor expression in these mice, that was lost in metabolically disturbed mice displaying lower ratios. This was functionally confirmed since mice with higher pre-stroke ratios displayed significantly better locomotor and cognitive performances, as validated by ROC analysis (AUC = 0.85). This study highlights pre-stroke ratios of plasma apelin to cholesterol or glucose as potential new biomarkers of post-stroke recovery.
Programmed axon degeneration gene variants in human disease.
Hopkins EL, Williams PA
Exp Neurol · 2026 Jun · PMID 42341897 · Publisher ↗
BACKGROUND: Programmed axon degeneration (PAD; also known as Wallerian degeneration) is a conserved pathway controlling axon breakdown following injury or metabolic stress. PAD is driven by the depletion of nicotinamide...
BACKGROUND: Programmed axon degeneration (PAD; also known as Wallerian degeneration) is a conserved pathway controlling axon breakdown following injury or metabolic stress. PAD is driven by the depletion of nicotinamide adenine dinucleotide (NAD) through loss of the pro-survival enzyme NMNAT2 and activation of the pro-degenerative NADase SARM1. Recent genetic studies have identified pathogenic variants in PAD pathway enzymes associated with severe neurodegenerative phenotypes. MAIN BODY: Pathogenic variants in NAMPT, NMNAT1, NMNAT2, and SARM1 have been identified and will be discussed in this review. NAMPT variants cause sensory and motor neuropathy with neurodevelopmental symptoms. NMNAT1 variants are well-characterized causes of Leber Congenital Amaurosis type 9, while NMNAT2 variants result in peripheral neuropathies with childhood onset. SARM1 gain-of-function variants with constitutively active NADase activity are enriched in amyotrophic lateral sclerosis patients. CONCLUSION: These findings demonstrate that maintaining proper NAD homeostasis is crucial for axon survival, and disruption through genetic variants leads to distinct neurodegenerative outcomes. Understanding these rare variants provides insight into PAD mechanisms and supports development of broad-spectrum neuroprotective therapies targeting this pathway. Current therapeutic approaches include SARM1 inhibitors in clinical trials, gene therapy, and NAD precursor supplementation, offering hope for treating multiple neurodegenerative diseases.
Molecular characteristics and modifications of glioblastoma affecting the efficacy of immunotherapy.
Zhang D, Liu P
Exp Neurol · 2026 Jun · PMID 42341896 · Publisher ↗
Glioblastoma is a highly aggressive brain tumor characterized by complex genetic, molecular, and epigenetic features that present significant challenges for treatment. This review explores recent advances in understandin...
Glioblastoma is a highly aggressive brain tumor characterized by complex genetic, molecular, and epigenetic features that present significant challenges for treatment. This review explores recent advances in understanding the molecular and epigenetic landscape of glioblastoma, with particular emphasis on epigenetic modifications such as DNA methylation, histone changes, and N6-methyladenosine regulation, including representative regulators such as AlkB homolog 5 and methyltransferase-like 14 that link tumor plasticity to immune evasion and therapeutic response. Accumulating evidence suggests that these modifications are associated with the regulation of gene expression, tumor progression, and immune evasion, and may influence the tumor's response to immunotherapy. The review further discusses the interplay between genetic mutations, such as those in Epidermal Growth Factor Receptor and Phosphatase and Tensin Homolog, and immune responses within the tumor microenvironment, which is characterized by immunosuppressive cell populations like regulatory T cells and myeloid-derived suppressor cells. By integrating molecular profiling, epigenetic analysis, and immunotherapy, researchers aim to develop personalized therapeutic strategies to enhance glioblastoma treatment outcomes. Additionally, the review highlights the potential of combining immunotherapy with targeted therapies and radiotherapy to overcome tumor resistance mechanisms. The use of advanced technologies, including single-cell sequencing and machine learning, is identified as crucial in uncovering the complexities of tumor-immune interactions, leading to more refined and effective treatment strategies. Ultimately, a comprehensive approach integrating genetic and epigenetic factors offers promising prospects for transforming glioblastoma into a more manageable condition, improving patient prognosis and quality of life.
Trem2 R47H mutation shows mild, but functionally divergent alterations in microglial phenotypes compared to Trem2 deficiency in aged App knock-in mice.
Shirotani K, Hatta D, Watanabe K … +3 more , Saito T, Saido TC, Iwata N
Exp Neurol · 2026 Jun · PMID 42341895 · Publisher ↗
The TREM2 R47H variant increases the risk of Alzheimer's disease (AD), yet its functional impact in aged mouse models remains incompletely understood. We generated a humanized Trem2 R47H knock-in (KI) line on the App bac...
The TREM2 R47H variant increases the risk of Alzheimer's disease (AD), yet its functional impact in aged mouse models remains incompletely understood. We generated a humanized Trem2 R47H knock-in (KI) line on the App background and compared it with a Trem2 knockout (KO) line to assess the degree of TREM2 functional impairment. Accumulation of amyloid β 42 and formation of dystrophic neurites were increased in Trem2 KO mice but not in Trem2 R47H KI mice at 18 or 24 months. qPCR and transcriptomic analyses revealed Trem2 KO mice showed deficits in upregulation of microglial genes while Trem2 R47H KI mice showed a response similar to control mice. Differential gene expression analysis identified altered expressions of genes responsible for ER stress/unfolded protein response and intracellular signalling in Trem2 R47H KI mice. Among the differentially expressed genes, Pmel and Gpnmb were or tended to be downregulated in Trem2 R47H KI as well as in Trem2 KO mice indicating their involvement in AD pathogenesis. These results clearly indicate that the TREM2 R47H variant confers a mild, rather than null, effect on microglial alterations during AD development and that Trem2 R47H KI mice should be used to understand pathological mechanism elicited by TREM2. Further identification and characterization of genes differentially expressed in Trem2 R47H KI mice will provide important insights into how the TREM2 risk variant modulates Alzheimer's disease-related pathology.
The skull bone marrow-meninges-brain axis: A new sentinel for neuroinflammation regulation in ischemic stroke.
Amin MR, Yu T, Cheng Z … +5 more , Zhang J, Chen G, Gu L, Jian Z, Xiong X
Exp Neurol · 2026 Jun · PMID 42335982 · Publisher ↗
The central nervous system (CNS) has long been regarded as relatively immune-privileged, but the discovery of glymphatic transport and meningeal lymphatic vessels has reshaped our understanding of neuroimmune communicati...
The central nervous system (CNS) has long been regarded as relatively immune-privileged, but the discovery of glymphatic transport and meningeal lymphatic vessels has reshaped our understanding of neuroimmune communication. In ischemic stroke, emerging evidence suggests that post-injury inflammation is regulated not only by systemic leukocyte recruitment and blood-brain barrier disruption but also by a spatially organized skull bone marrow-meninges-brain axis. Anatomical studies have identified vascular channels connecting calvarial bone marrow with the dura mater, providing a potential route for rapid communication between skull marrow immune niches and CNS border compartments. After ischemic injury, brain-derived inflammatory signals may activate adjacent skull marrow niches, while skull marrow-derived myeloid cells may migrate toward the meninges and contribute to early neuroinflammatory responses. In parallel, meningeal lymphatic vessels support the clearance of cerebrospinal fluid (CSF)-derived solutes, inflammatory mediators, antigens, and cellular debris toward deep cervical lymph nodes. This review integrates current evidence into a stage-dependent influx-efflux framework. In this model, skull-dura vascular channels may support local cellular influx and immune sensing, whereas meningeal lymphatic vessels provide a molecular and antigenic efflux pathway. The balance between these processes may influence edema formation, inflammatory amplification, immune resolution, and tissue repair after stroke. However, this axis remains an emerging concept rather than a fully established therapeutic target. Human evidence mainly supports anatomical plausibility and imaging accessibility, while direct demonstration of skull marrow-derived immune-cell trafficking in human stroke is still lacking. Further mechanistic, imaging, and translational studies are needed to determine whether this axis can guide precision monitoring and modulation of post-stroke neuroinflammation.
Neuroprotective activity of the α7-nAChR positive allosteric modulator PNU-120596 on short term outcomes after traumatic brain injury.
Winzer-Serhan UH, Ramakrishnan S, Li Y … +2 more , Mada S, Reddy DS
Exp Neurol · 2026 Jun · PMID 42335981 · Publisher ↗
Traumatic brain injury (TBI) often leads to long-lasting neurological, cognitive, and behavioral impairments. Despite its high global burden, no disease-modifying therapies currently exist to mitigate secondary injury pr...
Traumatic brain injury (TBI) often leads to long-lasting neurological, cognitive, and behavioral impairments. Despite its high global burden, no disease-modifying therapies currently exist to mitigate secondary injury processes that contribute to chronic neurological deficits. Activation of α7 nicotinic acetylcholine receptors (α7-nAChRs), which are expressed on neurons, glia, and immune cells, has been implicated in neuroprotection, modulation of neuronal excitability, and suppression of neuroinflammation. The present study investigated the efficacy of α7-nAChRs using the selective positive allosteric modulator PNU-120596 (PNU) on functional recovery and inflammatory responses. TBI was induced in adult mice using a cortical contusion injury model, which was followed by PNU (1 or 3 mg/kg, ip) treatment for six days. Neurological and behavioral outcomes were assessed using composite neuroscore, beam-walk, rotarod, burrowing, and health assessment tests. Serum inflammatory markers were measured using multiplex assays, hippocampal gene expression and glial activation markers by quantitative PCR. PNU treatment significantly improved neurological motor performance and motor coordination following TBI. In addition, PNU attenuated systemic inflammatory responses, reducing circulating levels of pro-inflammatory cytokines, including IFN-γ, GM-CSF, and IL-12. In the contralateral hippocampus, the lower dose of PNU normalized injury-induced increases in GFAP, IL-1β, and CXCL10 mRNA expression, indicating reduced astrogliosis and inflammatory signaling, whereas the higher dose was ineffective. Collectively, these findings demonstrate that potentiation of α7-nAChRs promotes dose-limited functional recovery and modulates inflammatory responses following TBI. Targeting α7-nAChR signaling may represent a promising therapeutic strategy to improve neurological outcomes after TBI.
Age-dependent effects of cannabidiol on cortical hyperexcitability in an experimental model of malformation of cortical development.
Martins de Lima T, Dos Santos FM, Schmidt Michel B … +4 more , Schonhofen P, Schroder N, Klamt F, Calcagnotto ME
Exp Neurol · 2026 Jun · PMID 42331276 · Publisher ↗
Malformations of cortical development (MCD) are major causes of refractory epilepsies, particularly in children. Cannabidiol (CBD) has demonstrated efficacy in treatment of refractory pediatric epilepsy syndromes. Howeve...
Malformations of cortical development (MCD) are major causes of refractory epilepsies, particularly in children. Cannabidiol (CBD) has demonstrated efficacy in treatment of refractory pediatric epilepsy syndromes. However, preclinical studies addressing its developmental stage-dependent effects, particularly in experimental models of MCD, remain limited. We evaluated the effects of CBD on induced hyperexcitability in cortical brain slices from Wistar rats with and without MCD at distinct developmental stages and examined whether alterations in endocannabinoid system (ECS) components are associated with CBD responsiveness. MCD was induced by bilateral cortical freeze lesion at postnatal day (P0-1) to generate microgyria in the somatosensory cortex. Local field potentials were recorded from cortical slices of juvenile (P21-30) and adolescent (P35-60) Sham and MCD rats. CBD was applied under three different timing paradigms to assess its effects on epileptiform activity induced by modified artificial cerebrospinal fluid containing 4-aminopiridine (4-AP) and 0 Mg (mACSF). Gene expression of ECS components was quantified in cortical tissue by RT-qPCR at both developmental stages. CBD co-applied with mACSF reduced short (>2-10 s) ictal events in slices from Sham and decreased prolonged (>100 s) ictal events in slices mainly from MCD animals at both ages. CBD did not attenuate pre-established hyperexcitability. However, pre-exposure to CBD delayed ictal onset, reduced overall ictal events frequency, particularly in juvenile Sham animals, and abolished long-lasting ictal events in slices from adolescent animals. Cortical samples from juvenile MCD animals exhibited increased gene expression of NAPE-PLD, MGLL, CB1R and CB2R, whereas DAGL was reduced in adolescence. CBD exerted age- and context-dependent modulatory effects on cortical hyperexcitability, with stronger preventive than therapeutic actions. Developmental stage, cortical organization and alterations in ECS components may influence CBD responsiveness. These findings highlight the importance of maturational, cortical network and molecular context when evaluating cannabinoid-based strategies for MCD-related refractory epilepsies.
Microglial HMGB1 drives hyperacute neuroinflammation and acute neuronal injury following cerebral ischemia-reperfusion by shaping early microglial inflammatory responses.
Lei K, Yang S, Chen H … +8 more , Dai J, Tan Q, Wang H, Du E, Min J, Lei J, Luo Y, Sun Y
Exp Neurol · 2026 Jun · PMID 42331275 · Publisher ↗
High-mobility group box 1 (HMGB1) is a nuclear protein that can act as a major damage-associated molecular pattern after cerebral ischemia-reperfusion (I/R). However, the cell-type-specific contribution of microglial HMG...
High-mobility group box 1 (HMGB1) is a nuclear protein that can act as a major damage-associated molecular pattern after cerebral ischemia-reperfusion (I/R). However, the cell-type-specific contribution of microglial HMGB1 to early neuroinflammatory responses during the hyperacute phase of stroke is not fully understood. Here, we investigated the role of microglial HMGB1 in early inflammatory activation using a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R) and microglia-specific HMGB1 conditional knockout mice (HMGB1). Acute neurological deficits, early ischemic lesion volume, microglial activation, inflammatory cytokine production, and neuronal integrity were evaluated at 6 h after reperfusion. In wild-type mice, hyperacute I/R induced rapid HMGB1 nuclear export, pronounced microglial activation with amoeboid-like morphology, increased TNF-α and IL-6 expression, and reduced TGF-β1 expression in vulnerable brain regions, including the medial prefrontal cortex and hippocampal CA1. Conditional deletion of microglial HMGB1 reduced early ischemic lesion volume, attenuated acute neurological deficits, dampened pro-inflammatory activation, decreased Iba1iNOS cell accumulation, partially preserved or increased anti-inflammatory marker expression, and alleviated neuronal injury. These findings suggest that microglial HMGB1 acts as an important microglia-derived early trigger that contributes to hyperacute neuroinflammatory amplification and acute neuronal damage after I/R. Targeting HMGB1 mobilization in microglia may represent a promising strategy for attenuating early inflammatory amplification after ischemia-reperfusion.
Protective effect of coumarin on diabetes-induced sciatic nerve damage in rats via TRPV1 modulation.
Yıldızhan K, Altındağ F, Bayir MH … +2 more , Keleş ÖF, Çınar R
Exp Neurol · 2026 Jun · PMID 42323959 · Publisher ↗
Diabetes-induced peripheral nerve damage is a major complication of chronic hyperglycemia, characterised by oxidative stress, inflammation, and apoptosis. The transient receptor potential vanilloid 1 (TRPV1) channel has...
Diabetes-induced peripheral nerve damage is a major complication of chronic hyperglycemia, characterised by oxidative stress, inflammation, and apoptosis. The transient receptor potential vanilloid 1 (TRPV1) channel has been identified as a key regulator linking these pathological processes. In this study, the neuroprotective effects of coumarin (CMR) on diabetic-induced sciatic nerve damage and its potential regulatory role on TRPV1 signalling pathways were investigated. Experimental diabetes was induced in Wistar rats by administering streptozotocin (45 mg/kg, i.p.), and the animals were given CMR (100 mg/kg/day, i.g.) for 14 days, beginning immediately after confirmation of diabetes (72 h post-STZ administration). Oxidative stress markers (GSH, MDA, SOD, CAT, NO), inflammatory cytokines (IL-1β, IL-6, TNF-α) and the transcription factor NF-κB, apoptotic markers (caspase-3, caspase-9, PARP-1), BDNF levels, and TRPV1 expression were evaluated in sciatic nerve tissues using biochemical, Western blot, and immunohistochemical methods. In the diabetic group, oxidative stress, inflammation, apoptosis, and TRPV1 expression were significantly increased, while antioxidant capacity and BDNF levels were decreased (p < 0.05). CMR treatment significantly reversed these changes, restoring redox balance, suppressing pro-inflammatory and apoptotic pathways, and increasing BDNF levels (p < 0.05). Furthermore, the diabetes-induced upregulation of TRPV1 was significantly attenuated. Histopathological findings showed structural improvement in sciatic nerve tissue and decreased glial activation. In conclusion, CMR exerts a significant neuroprotective effect against diabetes-induced sciatic nerve damage by modulating TRPV1-associated oxidative, inflammatory, and apoptotic pathways, highlighting its potential as a targeted therapeutic candidate.
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