Exp. Neurol. [JOURNAL]
Sun
200 papers
Modulating inflammasome (NLRP3) activation and stress granule (SG) formation: Insight of neuroprotection by Normobaric oxygen (NBO) in ischemic stroke.
Guo S, Cheng Z, Al Tekreeti A … +3 more , Li F, Ding Y, Geng X
Exp Neurol · 2026 Jun · PMID 42320692 · Publisher ↗
BACKGROUND: NBO therapy has demonstrated a neuroprotective effect on ischemic stroke. This study investigated the role of HIF-1α in regulating SG formation and NLRP3 inflammasome activation following I/R injury in NBO-in...
BACKGROUND: NBO therapy has demonstrated a neuroprotective effect on ischemic stroke. This study investigated the role of HIF-1α in regulating SG formation and NLRP3 inflammasome activation following I/R injury in NBO-induced neuroprotection. METHODS: A total of 137 adult male SD rats underwent 2 h of MCAO, followed by 2, 6, 24 or 48 h of reperfusion. NBO (95% O₂ at 2 l/min) was administered for 2 h at the onset of reperfusion. HIF-1α inhibitor (YC-1) was administered 2 h before MCAO. Brain damage was assessed by infarct volumes (TTC staining), LDH and ROS levels (ELISA), and apoptotic and pyroptosis cell death (flow cytometry and TUNEL assay). Gene and protein levels of HIF-1α and inflammasome related factors (IL-18, IL-1β, NLRP3, cleaved-Caspase-1, GSDMD-N, ASC, TXNIP) were analyzed. SG proteins levels (G3BP1, TIA-1) and DDX3X were detected by Western blot. Co-IP detected the interaction between DDX3X and G3BP1 or NLRP3. RESULTS: Infarct volume, LDH expression, ROS levels, and cell death (apoptosis and pyroptosis) were significantly increased after I/R injury. NBO and YC-1 treatments significantly reduced infarct volume, LDH and ROS levels, and cell death at 24 and 48 h of reperfusion. NBO suppressed the expression of inflammasome-related markers (IL-1β, IL-18, NLRP3, TXNIP, ASC, cleaved-Caspase-1, GSDMD-N) at both mRNA and protein levels. Co-IP analysis showed that I/R enhanced the interaction between DDX3X and NLRP3, which was suppressed by NBO and YC-1. NBO increased SG formation by regulating G3BP1 and TIA-1 expression and strengthened the interaction between DDX3X and G3BP1. NBO + YC-1 did not show additive effects, indicating that the two treatments act through the same HIF-1α-dependent pathway. CONCLUSION: NBO exerts strong neuroprotection against ischemic stroke by inhibiting HIF-1α-mediated NLRP3 inflammasome activation and enhancing SG formation via DDX3X-G3BP1 interaction. This study identifies HIF-1α as a key mediator of post-ischemic inflammation and stress response, highlighting NBO as a potent, mechanism-based therapeutic in ischemic stroke.
Machine learning-assisted prediction of PANoptosis-related molecular targets and precise screening of neuroprotective drugs for spinal cord injury.
Wang D, Wang R, Liao H … +7 more , Lu F, Guo Z, Xu R, Chen A, Niu Z, Ou Y, Li G
Exp Neurol · 2026 Jun · PMID 42309342 · Publisher ↗
Spinal cord injury (SCI) is a highly disabling central nervous system disease with complex pathology, and targeted neuroprotective drugs remain clinically lacking. However, traditional molecular target screening and drug...
Spinal cord injury (SCI) is a highly disabling central nervous system disease with complex pathology, and targeted neuroprotective drugs remain clinically lacking. However, traditional molecular target screening and drug prediction methods are inefficient, costly, and poorly targeted, failing to meet clinical precision treatment needs. To address this, we introduced machine learning to construct a multi-dimensional data integration framework. First, we established normal, acute- and subacute-phase SCI mouse complete transection models, and RNA-seq combined with single-cell sequencing revealed acute-phase may occur extensive neuronal PANoptosis. Using WGCNA and MCC algorithms, 25 candidate genes for extensive neuronal PANoptosis in the acute phase were screened out. Then, we comprehensively applied machine learning algorithms including Elastic Net-GLM, Random Forest, Support Vector Machine, and LASSO to predict and prioritize potential molecular targets, identifying 13 possible core genes for extensive neuronal PANoptosis, including Tacc3, Aurka, Mcm6, Mcm5, Ripk1, etc. With the help of the Connectivity Map, drug prediction was performed on these 13 genes, and the 8 candidate drugs with neuroprotective effects were screened out. Through protein domain screening, it was verified via proof-by-contradiction assays that the drug Xaliproden can establish robust interactions with the 7XMK, 7FCZ and 7FD0 domains of Ripk1, a core molecule of the PANoptosome, via a network of multiple hydrogen bonds. This finding provides a novel screening strategy for neuroprotective drugs for spinal cord injury and is of great significance for promoting the establishment of a precision treatment system for the acute phase of injury.
Hypertonic saline protects the axo-myelinic interface acutely after contusive SCI and improves postural stability and balance as revealed by motion sequencing (MoSeq).
Cortez-Thomas F, Morehouse J, Hill N … +2 more , Jones E, Stirling DP
Exp Neurol · 2026 Jun · PMID 42309341 · Publisher ↗
The development of periaxonal swellings and separation of the axo-myelinic interface are prominent features acutely post-contusive spinal cord injury (SCI) and are associated with ongoing secondary degeneration of myelin...
The development of periaxonal swellings and separation of the axo-myelinic interface are prominent features acutely post-contusive spinal cord injury (SCI) and are associated with ongoing secondary degeneration of myelinated fibers. However, the molecular and cellular mechanisms remain poorly understood. Given the temporal overlap between vascular edema formation after SCI and periaxonal swelling, we hypothesized that hypertonic saline (HTS) treatment would reduce periaxonal swelling and protect myelinated fibers after SCI. To test this hypothesis, we used longitudinal intravital two-photon excitation microscopy to simultaneously image dorsal column axons and their myelin sheath using Thy1 mice and the lipophilic fluorescent dye Nile red respectively. We found that low-dose HTS (3%) given at 1, 3, or 6 h following a contusive SCI (T13, 30 kilodyne, IH Impactor) significantly reduced periaxonal swellings and increased axonal survival at 24 h compared to normal saline (NS, 0.9% NaCl) treated controls. In distinction, delayed treatment of 5% HTS beginning at 6 h after SCI was less effective. To determine whether 3% HTS treatment initiated at 6 h following a T9, 50 kilodyne contusive SCI improves neurological recovery we used a standard open-field behavioral test (Basso Mouse Scale, BMS) and horizontal ladder. We also applied Motion Sequencing (MoSeq), an unsupervised machine learning method, to further assess behavioral changes due to SCI and the effects of HTS treatment. BMS scoring, and proportional analysis of BMS subscores revealed subtle improvements in functional recovery between HTS and NS treatment. In addition, MoSeq analysis unveiled novel differences in behavior between normal and SCI mice and identified enhanced recovery trajectories in locomotor behaviors following 3% HTS treatment. Collectively, these findings indicate that low-dose HTS confers acute protection to myelinated fibers following SCI through attenuation of edema-associated alterations within the periaxonal space and preservation of axonal integrity. However, the extent to which HTS treatment alone translates into robust functional recovery remains to be determined.
Proteomics reveal PTEN as a critical mediator of sustained mitochondrial dysfunction during chronic spinal cord injury.
Patel SP, Gartner CA, Patience M … +13 more , Patel J, Slone VK, Capes DE, Iyer K, Zapata-Jaramillo MF, Kota V, Hash MT, Salazar J, Chatterton MP, Tree MO, Petersen ED, Vary CP, Stewart AN
Exp Neurol · 2026 Jun · PMID 42309340 · Publisher ↗
Activity of the phosphatase and tensin homologue protein (PTEN) remains elevated in neurons chronically after spinal cord injury (SCI) and suppresses tissue repair. However, PTEN may also disrupt other neuronal functions...
Activity of the phosphatase and tensin homologue protein (PTEN) remains elevated in neurons chronically after spinal cord injury (SCI) and suppresses tissue repair. However, PTEN may also disrupt other neuronal functions not directly related to regeneration. To better understand the role of PTEN on neuronal functions in chronic SCI, neuronal-specific PTEN-KO was induced using spinal injections of retrogradely-transported AAVs (AAVrg) immediately after contusion SCI in mice. Spinal cords were harvested at 6 weeks post-injury and untargeted total proteomics was performed. Bioinformatics analyses revealed a downregulation of mitochondrial-associated proteins in chronic SCI that was reversed after PTEN-KO. We replicated the experimental conditions to validate the effects of chronic SCI ± PTEN-KO on mitochondrial functions using ex vivo respiratory testing on whole-spinal cord mitochondrial isolates. Mitochondrial respiratory capacity was reduced in chronic SCI and was restored after PTEN-KO. Next, we evaluated the extent to which chronic SCI specifically affects neuronal mitochondria and whether PGC1α upregulation can restore respiratory capacity. We designed an AAVrg vector to enable a magnetic bead pulldown approach to isolate neuron-specific mitochondria with, or without, concurrent PGC1α upregulation. AAVrg vectors were delivered into the spinal cord at 15-weeks post-injury, and neuron-specific mitochondria were isolated 6-weeks later. Neuronal mitochondria present a ∼ 50% loss of respiratory capacity in chronic SCI that was restored with PGC1α upregulation. Collectively, we demonstrate that mitochondrial respiratory abilities are significantly repressed chronically after SCI, that PTEN is a major contributor to sustained mitochondrial dysfunction, and that PGC1α upregulation can restore mitochondrial bioenergetic abilities during chronic SCI. SIGNIFICANCE STATEMENT: Chronic spinal cord injury (SCI) is hallmarked by sustained motor and sensory dysfunction with little potential for repair. The chronic SCI environment limits the excitability of spared neural circuits and significantly reduces the regenerative potential of exogenously applied therapeutics. Through a series of experiments, we have derived a novel and significant observation that neuronal mitochondria exhibit a ∼ 50% loss of respiratory abilities chronically after SCI in mice. Moreover, by knocking out PTEN, a protein known to be chronically hyperactive after SCI, we demonstrate the ability to restore mitochondrial respiratory abilities. Our discoveries highlight a novel and vital pathological mechanism that is sustained chronically after SCI that is mediated by neuronal PTEN activity.
From molecular mechanisms to clinical implications of clock genes in ischemic stroke: A scoping review.
Li S, Liu K, Lv Y … +7 more , Zhang Z, Liu Y, Yu M, Yang Q, Gao Q, Zhao Y, Wu H
Exp Neurol · 2026 Jun · PMID 42309339 · Publisher ↗
BACKGROUND: Sleep and circadian rhythms are closely linked to ischemic stroke (IS) risk and outcomes; however, the molecular mechanisms underlying this relationship remain incompletely understood. This scoping review foc...
BACKGROUND: Sleep and circadian rhythms are closely linked to ischemic stroke (IS) risk and outcomes; however, the molecular mechanisms underlying this relationship remain incompletely understood. This scoping review focuses on the roles of clock genes in IS, integrating evidence from animal and human studies. METHODS: This scoping review followed the PRISMA guidelines. We searched eight English and Chinese databases (up to May 10, 2026) for human and animal studies examining the role of circadian clock genes in ischemic stroke onset, progression, or prognosis. Data related to the study design, specific clock genes, and key outcomes were extracted. Primary studies and review articles were synthesized separately to minimize aggregation bias. This scoping review followed the PRISMA-ScR guidelines. RESULTS: 19 studies were included: 9 animal model studies, 2 human case-control studies, and 8 review articles. Primary evidence suggests that clock genes may influence stroke susceptibility and severity. Notably, the PER1 rs2253820 variant was associated with increased IS risk. Ischemic stroke might also alter the expression of PER1 and CRY1, leading to imbalances in sleep-wake architecture. Circadian variations in stroke severity may be related to the expression of clock genes. This relationship was also influenced by age and gender. CONCLUSIONS: Clock genes may influence the brain's response to ischemic stress. Large-scale human studies are still needed to confirm the two-way relationship between stroke and clock genes before these gene polymorphisms can be used for prediction or treatment.
Severe neonatal epilepsy linked to a novel homozygous SLC12A5 Arg508Cys variant with impaired chloride transport.
Ghalamkari S, Jӓrvelӓ V, Hartmann AM … +9 more , Merő G, Hudák R, Mótyán JA, Szakszon K, Huttula M, Uusimaa J, Immonen EV, Medina I, Balogh I
Exp Neurol · 2026 Jun · PMID 42309338 · Publisher ↗
The potassium-chloride cotransporter 2 (KCC2) is a neuron-specific transporter essential for maintaining low intracellular chloride levels. By extruding chloride ions, KCC2 ensures that activation of GABA receptors produ...
The potassium-chloride cotransporter 2 (KCC2) is a neuron-specific transporter essential for maintaining low intracellular chloride levels. By extruding chloride ions, KCC2 ensures that activation of GABA receptors produces hyperpolarizing inhibitory responses rather than depolarizing responses. Disruption of KCC2 function can therefore impair GABAergic signaling and neuronal maturation, contributing to a range of neurodevelopmental and neurological disorders. Pathogenic biallelic variants in SLC12A5, the gene encoding KCC2, are a rare cause of severe early-onset developmental and epileptic encephalopathies, including epilepsy of infancy with migrating focal seizures (EIMFS). Here, we describe a novel homozygous SLC12A5 variant identified in a patient with severe, drug-resistant epilepsy, neonatal encephalopathy, and rapid neurological deterioration. Combined Western blot, thallium (Tl) flux, and gramicidin-perforated patch-clamp assays revealed significantly reduced ion-transport function of the KCC2 construct encoding the variant, with no change in protein expression abundance or profile. Live-cell surface immunolabeling demonstrated markedly reduced plasma membrane expression and decreased internalization of the variant, suggesting that the functional deficit primarily results from defective trafficking or reduced membrane stability. These findings expand the spectrum of KCC2-related disorders and highlight the critical role of KCC2 in early brain development. By linking a specific SLC12A5 variant to impaired chloride homeostasis and neuronal hyperexcitability, this study provides mechanistic insight into disease pathogenesis and lays the groundwork for therapeutic strategies aimed at restoring or stabilizing KCC2 function.
Advances in the application of photobiomodulation technology in spinal cord injury rehabilitation.
Yang L, Liu J, Qiao Q … +4 more , Zhou J, Zhang Z, Gao Y, Liu Y
Exp Neurol · 2026 Jun · PMID 42297204 · Publisher ↗
Spinal cord injury (SCI) is a severe central nervous system trauma that often leads to irreversible motor, sensory, and autonomic dysfunction, posing significant challenges to both patients' quality of life and the publi...
Spinal cord injury (SCI) is a severe central nervous system trauma that often leads to irreversible motor, sensory, and autonomic dysfunction, posing significant challenges to both patients' quality of life and the public healthcare system. Photobiomodulation (PBM), a non-invasive, low-risk physical therapy technique, activates intracellular photoacceptors with specific wavelengths of light (primarily near-infrared and red light). By regulating pathways involved in oxidative stress, inflammation, and neural repair, PBM offers a novel approach to SCI rehabilitation. This paper systematically reviews the mechanisms of PBM and summarizes the evidence for its application in the recovery of motor, sensory, and reproductive functions, as well as in autonomic dysfunction following SCI. What's more, it analyzes the efficacy and safety of PBM in combination with other interventions and outlines future research priorities in this field, aiming to guide the clinical translation and application of PBM in SCI rehabilitation.
The leaked mitochondrial DNA activated the cGAS-STING signaling pathway and exacerbated the motor dysfunction in mice caused by MPTP.
Zhu G, Yu X, Guo Y … +8 more , Yang L, Yang Q, Xu W, Yang J, Zhang R, Lin L, Ouyang C, Zhang L
Exp Neurol · 2026 Jun · PMID 42288132 · Publisher ↗
Parkinson's disease (PD) is the fastest-growing neurological disorder worldwide, outpacing even the rate of population aging. The Global Burden of Disease Study estimated that more than 10 million individuals were affect...
Parkinson's disease (PD) is the fastest-growing neurological disorder worldwide, outpacing even the rate of population aging. The Global Burden of Disease Study estimated that more than 10 million individuals were affected in 2020, a figure projected to double by 2040. Pathologically, PD is characterised by the progressive degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). Although early mechanistic work centred on gross anatomical changes and neuronal injury, converging evidence now positions neuroinflammation as an early and causal driver of DA neurodegeneration across the entire PD continuum. While cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent innate immune signaling has been implicated in several neurodegenerative disorders, its contribution to PD has remained undefined. Here, using complementary in vitro and in vivo PD models, we demonstrate that mitochondrial stress triggers mitochondrial DNA (mtDNA) leakage into the cytosol, thereby activating the cGAS-STING pathway and precipitating SNc neuronal loss and overt motor dysfunction. Genetic knockdown of STING markedly attenuated DA neuronal demise and preserved motor performance, identifying STING-mediated neuroinflammation as a critical mediator of DAergic neurodegeneration in MPTP-induced motor deficits. Collectively, our data indicate that selective inhibition of the cGAS-STING inflammatory cascade robustly mitigates MPTP-induced nigrostriatal DA neurodegeneration and motor deficits in mice, and nominate this pathway as a tractable therapeutic target for disease-modifying intervention in PD.
Convergence and innovative applications of cutting-edge biomedical technologies in brain organoid research.
Zhang Z, Wang Y, Chen L … +1 more , Ming D
Exp Neurol · 2026 Jun · PMID 42285251 · Publisher ↗
Brain organoids, as three-dimensional cellular models that recapitulate human brain development and function in vitro, have emerged as a pivotal platform for neuroscience research. However, it still faces many technical...
Brain organoids, as three-dimensional cellular models that recapitulate human brain development and function in vitro, have emerged as a pivotal platform for neuroscience research. However, it still faces many technical challenges in aspects such as the structural and physiological relevance, functional regulation and system analysis, and urgently needs the deep integration of multi-disciplinary technologies to drive paradigm-shifting innovations. Here, we systematically summarize the main technological frameworks that support brain organoid research, including bioengineering and organoid construction technologies, biofabrication and microenvironmental modulation strategies, high-precision detection and multimodal analytical methodologies, as well as intelligent algorithms and data analysis platforms. The cross-integration of multiple technologies not only provides solutions to the existing limitations in brain organoid research, but also opens up cross-technological innovation application scenarios. We further discuss key bottlenecks in technology convergence and propose the development direction of future research. This review aims to provide a comprehensive technical roadmap for brain organoid research, promoting its in-depth application and paradigm innovation in cross-disciplinary fields including neuroscience, precision medicine, and brain-inspired computing.
Infarct-associated oligoclonal T cell expansion in chronic experimental stroke across age, sex, and models.
Kumar SS, Chapman ED, Becktel DA … +22 more , Whitman SA, Crumpacker R, Zbesko JC, Berchtold D, Dames C, Cuartero MI, Garcia-Culebras A, Hegarty LM, Brezzo G, Goertz JE, Zera K, Smith CJ, Allan SM, Meisel C, Meisel A, Moro MÁ, McColl BW, Anrather J, Buckwalter MS, Morrison HW, Schnellmann RG, Doyle KP
Exp Neurol · 2026 Jun · PMID 42285250 · Full text
Ischemic stroke induces prolonged T cell accumulation within injured brain tissue, yet it remains unclear whether these cells reflect nonspecific inflammatory persistence or organized adaptive immune responses. To define...
Ischemic stroke induces prolonged T cell accumulation within injured brain tissue, yet it remains unclear whether these cells reflect nonspecific inflammatory persistence or organized adaptive immune responses. To define the clonal architecture of post-stroke T cells, we performed genomic DNA-based bulk T cell receptor (TCR) immunosequencing of CDR3α and CDR3β repertoires from infarcted brain and spleen during the chronic phase of experimental stroke across age and sex. TCRβ repertoires were further examined across three ischemic stroke models reproduced independently at sites in the United States and Europe. Chronic infarct tissue consistently exhibited oligoclonal T cell expansion across age, sex, stroke models, and laboratories; spleen and blood remained broadly polyclonal. Dominant clonotypes occupied a substantial fraction of the infarct repertoire, revealing a structured clonal architecture within the injured brain. Computational annotation identified recurrent sequence similarities to self-associated TCRs, including receptors linked to myelin, nuclear, and insulin-related antigens, although many expanded clonotypes lacked database matches. These annotations are presented as hypothesis-generating rather than evidence of antigen specificity. Together, these findings demonstrate that chronic ischemic brain injury is associated with a reproducible, infarct-associated clonal T cell signature whose conserved architecture is consistent with antigen-driven selection, although stochastic or cytokine-driven expansion cannot be excluded. The accompanying publicly available TCR repertoire dataset provides a clonotype-resolved reference resource for future investigations of antigen specificity and adaptive immune dynamics in chronic post-stroke neuroinflammation.
HSPA1-regulated mitophagy-necroptosis crosstalk determines the fate of brain microvascular endothelial cells after cerebral ischemia.
Yang Q, Wu Y, Zhao H … +1 more , Zhang Q
Exp Neurol · 2026 Jun · PMID 42285249 · Publisher ↗
Ischemic stroke triggers brain microvascular endothelial dysfunction. Necroptosis (RIP3-MLKL) and PINK1-Parkin mitophagy are both implicated, but their coordination and the role of HSPA1/HSP70 remain unclear. Using oxyge...
Ischemic stroke triggers brain microvascular endothelial dysfunction. Necroptosis (RIP3-MLKL) and PINK1-Parkin mitophagy are both implicated, but their coordination and the role of HSPA1/HSP70 remain unclear. Using oxygen-glucose deprivation (OGD) in hCMEC/D3 cells and a rat permanent middle cerebral artery occlusion (pMCAO) model, we tested whether stress-inducible HSPA1 mediates a mitochondrial "tug-of-war" between necroptosis and mitophagy. Time-course analysis identified a 4-h OGD window in which RIP3/MLKL activation and mitochondrial MLKL oligomerization peaked, while PINK1-Parkin and HSPA1 increased later. Within this window, necrostatin-1 (Nec-1) suppressed RIP3/MLKL signalling and mitochondrial MLKL oligomers, improved cell viability, and partially reshaped mitophagy markers. Rapamycin (RAPA) improved viability, upregulated PINK1, LC3-II/LC3-I and HSPA1, and reduced mitochondrial MLKL oligomers despite increased total RIP3/MLKL, consistent with enhanced autophagy and attenuated necroptotic execution. The mitochondrial HSP70 inhibitor MKT-077 reduced both MLKL oligomers and PINK1, suggesting that both pathways may be influenced by HSPA1-related activity. In pMCAO rats, Nec-1 and MKT-077, and to a lesser extent RAPA, improved neurological outcomes and reduced infarct volume; immunofluorescence further revealed increased necroptosis- and mitophagy-related signals in the peri-infarct cortex, with overlapping MLKL and PINK1 signals observed in CD31-positive endothelial cells/microvascular structures. Collectively, HSPA1 may function as a shared and limited chaperone resource that shifts from supporting necroptosis early to facilitating mitophagy as its abundance rises, thereby protecting endothelium after cerebral ischemia.
Systemic characterization of aging-related phenotypes induced by wild-type and G2019S LRRK2 in Caenorhabditis elegans.
Li C, Shi FY, He XX … +6 more , Xiong SY, Gu L, Wu GS, Hou PP, Huang C, Luo HR
Exp Neurol · 2026 Jun · PMID 42270006 · Publisher ↗
BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2), initially identified as a gene implicated in Parkinson's disease, is increasingly recognized for its influence on aging and associated disorders. However, its systemic ro...
BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2), initially identified as a gene implicated in Parkinson's disease, is increasingly recognized for its influence on aging and associated disorders. However, its systemic roles in biological aging remain poorly understood. METHODS: To assess its physiological roles, we utilized Caenorhabditis elegans models with pan-neuronal expression of either wild-type or G2019S-mutant human LRRK2. Aging-related phenotypes were evaluated through analyses of development, metabolic activity, oxidative stress response, behavior, neuronal integrity, and proteostasis. Transcriptomic and untargeted metabolomic profiling were conducted to elucidate the molecular consequences of LRRK2 expression and mutation. RESULTS: Wild-type LRRK2 enhanced organismal growth, metabolic activity, and resistance to oxidative and heat stress, while simultaneously inducing mild neurodegenerative alterations. In contrast, the G2019S mutation substantially aggravated aging-associated phenotypes, including reduced lifespan, increased lipid and lipofuscin accumulation, and heightened dopaminergic vulnerability under stress conditions. Multi-omics analyses further showed that wild-type LRRK2 predominantly upregulated pathways related to energy metabolism and specific components of proteostasis, whereas G2019S resulted in diminished amino acid availability, disrupted protein homeostasis, and more pronounced metabolic dysregulation. CONCLUSIONS: Our findings support a bidirectional role of LRRK2 in aging: wild-type LRRK2 promotes systemic metabolic activation and stress resistance but increases neuronal susceptibility, while the G2019S mutation further amplifies metabolic and structural vulnerability. These effects are strongly tissue-dependent and modulated by mutational background. Collectively, this study expands the role of LRRK2 from a Parkinson's disease-associated protein to a multisystem regulator of aging, providing mechanistic insight and a basis for tissue-selective LRRK2-targeted interventions for age-related disorders.
Aged oligodendrocyte progenitors retain the capacity to respond to an inflammatory insult.
Fresenko EE, Kaiser KE, Burson BJ … +9 more , Bahri CN, Ahmed NF, Bozik JB, Packer D, Tabor BJ, Beirowski B, Wedemeyer MA, Sun W, Harrington CA
Exp Neurol · 2026 Jun · PMID 42270005 · Publisher ↗
Aging is associated with neurodegeneration and progressive disability in people living with multiple sclerosis (MS). Aged oligodendrocyte progenitor cells (OPCs) exhibit slower differentiation and remyelination coupled w...
Aging is associated with neurodegeneration and progressive disability in people living with multiple sclerosis (MS). Aged oligodendrocyte progenitor cells (OPCs) exhibit slower differentiation and remyelination coupled with upregulation of senescence pathways, both in physiological aging and toxin-mediated murine models. The impact of auto-immune demyelinating environment on young and aged OPCs has not been explored. This study combined a genetic OPC lineage tracing approach in young and middle-aged animals with adoptive transfer of MOG-reactive Th17 T cells to determine how aging influences OPC localization, differentiation and remyelination in an autoimmune environment as well as mature oligodendrocyte survival. Lineage traced OPCs were enriched within lesions compared to non-lesion white matter in both age groups and proliferating OPCs were concentrated at lesion edges. Regardless of age, differentiation of lineage traced OPCs into mature OLs was rare and lowest within lesions. Differentiated OLs were reduced in adoptive transfer, particularly in middle-aged animals, and mature OLs were undergoing cell death within lesions and at meningeal borders. Remyelination was present in lesions from both young and middle-aged animals at this acute timepoint. These findings reveal that an autoimmune inflammatory environment stimulated both young and aged OPCs to proliferate near lesion borders, increase their density lesions, undergo differentiation and remyelinate axons. Differentiated OLs were susceptible to cell death within the lesion environment likely due to cytotoxic MOG-reactive T cells. The rapid and robust response of both OPCs in both age groups suggests that autoimmune-mediated demyelination and the inflammatory lesional environment may directly promote OPC recruitment, proliferation, and differentiation. Identifying cell intrinsic pathways in OPCs that promote OPC and newly formed OL survival during an inflammatory challenge will inform the development of remyelination therapies in MS.
Animal models of multi-infarct dementia: Methodological approaches, neuropathology, functional outcomes, and translational relevance.
Liu Z, Zhang ZG, Chopp M
Exp Neurol · 2026 Jun · PMID 42250678 · Full text
Multi-infarct dementia (MID) is a major subtype of vascular cognitive impairment, second only to Alzheimer's disease as a leading cause of dementia worldwide. Unlike neurodegenerative dementias, MID results from recurren...
Multi-infarct dementia (MID) is a major subtype of vascular cognitive impairment, second only to Alzheimer's disease as a leading cause of dementia worldwide. Unlike neurodegenerative dementias, MID results from recurrent vascular insults, producing stepwise cognitive decline. Animal models have become indispensable for understanding MID mechanisms and testing therapies, yet no single model fully captures human disease complexity. This review synthesizes current knowledge of embolic, chronic cerebral hypoperfusion, hypertensive, and large animal models of MID. We compare methodological strategies, neuropathological features (including white matter injury, neuroinflammation, and blood-brain barrier disruption), and behavioral outcomes. Key limitations include poor replication of infarct heterogeneity, absence of comorbidities, and translational failures. Emerging directions such as multi-hit paradigms and mixed dementia models are discussed. We conclude that integrative, multifactorial models are essential for improving translational relevance and developing effective therapies.
PARP1 modulates BBB function via regulating NLRC5 in cerebral endothelial cells during ischemic stroke.
Yang X, Shu H, Liang M … +2 more , Tao C, Zhu X
Exp Neurol · 2026 Jun · PMID 42235665 · Publisher ↗
Ischemic stroke (IS) is one of the major causes of morbidity and mortality worldwide. Blood-brain barrier (BBB) dysfunction acts as an important alteration after IS, however, the underlying pathophysiological mechanisms...
Ischemic stroke (IS) is one of the major causes of morbidity and mortality worldwide. Blood-brain barrier (BBB) dysfunction acts as an important alteration after IS, however, the underlying pathophysiological mechanisms remain incompletely delineated. Endothelial cells are the primary constituents of BBB. In this study, we demonstrated that NOD-like receptor family CARD domain containing 5 (NLRC5) was markedly decreased in brain endothelial cells after IS and the Adeno-Associated Virus Serotype 9 (AAV9)-inducted endothelial cell-specific knockdown of NLRC5 further aggravates BBB dysfunction, neurological function, delays cerebral blood flow recovery and promotes neuroinflammation. Immunoprecipitation-mass spectrometry and co-immunoprecipitation demonstrate the interaction between NLRC5 and Poly (ADP-ribose) polymerase 1 (PARP1), which resulted in the downregulation of NLRC5. Mechanistically, PARP1-mediated PARylation of NLRC5 enhanced its ubiquitination, thereby promoted NLRC5 proteasomal degradation. By using PJ34, a specific inhibitor of PARP1, IS induced BBB dysfunction was alleviated. Collectively, our study provided a novel mechanistic insight into how PARP1 impacts BBB function in IS and identified PARP1 inhibitor as a promising therapeutic strategy for IS.
Etiology-specific trajectories of longitudinal functional connectivity and network topology in posttraumatic and mesial temporal lobe epileptogenesis.
Jafari N, Yeh HJ, Kumar U … +5 more , Harris NG, Stern JM, Engel J, Bragin A, Li L
Exp Neurol · 2026 Jun · PMID 42229742 · Publisher ↗
The latent period of epileptogenesis represents a critical window for early diagnosis and preventive intervention before the disease progresses. Among epilepsy subtypes, posttraumatic epilepsy (PTE) and mesial temporal l...
The latent period of epileptogenesis represents a critical window for early diagnosis and preventive intervention before the disease progresses. Among epilepsy subtypes, posttraumatic epilepsy (PTE) and mesial temporal lobe epilepsy (mTLE) account for a significant proportion of cases. However, it remains unclear whether these two subtypes share common longitudinal network biomarkers during the latent phase. To address this question, we performed longitudinal functional and structural MRI in rat models of PTE induced by lateral fluid percussion injury (LFPI) and mTLE induced by intrahippocampal kainic acid (KA). The final dataset included 31 rats, comprising 18 KA/mTLE rats and 13 LFPI/PTE rats, with available MRI scans at pre-induction baseline, 1 week, and/or 8 weeks post-induction. We quantified lesion volume (LV), resting-state functional connectivity (rsFC), network topology, longitudinal changes, and rsFC-LV associations. In mTLE model, hippocampal rsFC increased at 1 week relative to baseline (p = 0.024) and declined globally at 8 weeks. Hippocampal rsFC was negatively associated with LV in the left hippocampus (week 1, p = 0.036), right hippocampus (week 8, p = 0.02), and sensorimotor cortex (week 8, p = 0.041). Network topology showed an early reduction followed by a later increase in clustering coefficient. In contrast, the PTE model displayed progressive rsFC reductions from baseline at both post-induction time points and higher clustering coefficient than mTLE. Despite overall rsFC declines in both models, mTLE retained greater prefrontal rsFC but lower hippocampal rsFC than PTE at 8 weeks. Etiology-specific LV differences were observed in hippocampus and sensorimotor cortex at week 8 (mTLE < PTE, p < 0.037). These findings demonstrate distinct, etiology-specific trajectories of rsFC, topology, and structure-function coupling in established rodent models of epileptogenesis.
Impact of acute high thoracic spinal cord injury on in vivo vascular function in rats.
Kafashi M, Wearing OH, Erskine E … +5 more , Foster GE, Polichnowski AJ, Krassioukov A, Rajaei A, West CR
Exp Neurol · 2026 May · PMID 42219075 · Publisher ↗
Cardiovascular dysfunction is a major cause of morbidity and mortality following high-thoracic spinal cord injury (SCI), yet the acute impact of SCI on integrated neurovascular control remains poorly defined. In the curr...
Cardiovascular dysfunction is a major cause of morbidity and mortality following high-thoracic spinal cord injury (SCI), yet the acute impact of SCI on integrated neurovascular control remains poorly defined. In the current study, we aimed to investigate the acute effects of complete T3 transection (T3-SCI) on in vivo hemodynamic function, superior mesenteric artery (SMA) autoregulation, sympathetic baroreflex sensitivity (sBRS), and sympathetic vascular transduction (SVT) in anesthetized rats. Nineteen male Wistar rats were randomized into naïve control (n = 10) or T3-SCI (n = 9) experimental groups. Rats were anesthetized with intravenous urethane, and arterial blood pressure (ABP), SMA blood flow (Q), and splanchnic sympathetic nerve activity (sSNA) were simultaneously recorded. SMA autoregulation was evaluated using controlled venous blood withdrawal and reinfusion. sBRS was assessed via graded phenylephrine infusion, and SVT was quantified by analyzing mean arterial pressure (MAP), Q, and SMA conductance (C) responses to sSNA bursts. We found that T3-SCI exhibited lower resting sSNA, MAP, heart rate (HR), and diastolic Q compared to naïve (all P < 0.03). Despite this, dynamic SMA autoregulation remained intact in T3-SCI, as evidenced by preserved lower limit of autoregulation and autoregulation index. However, sBRS was completely abolished in T3-SCI rats, which, unlike naïve rats, did not suppress sSNA in response to PE-induced increases in ABP. Furthermore, signatures of SVT were markedly attenuated in T3-SCI. This study demonstrates that while dynamic SMA autoregulation is acutely preserved in T3-SCI, loss of supraspinal sympathetic control results in immediate and significant impairments in splanchnic/mesenteric sympathetic arterial tone, SVT and baroreflex function.
circCrebrf modulates the miR-3562/ERLIN1 axis to suppress neuronal oxidative stress and apoptosis following traumatic brain injury.
Li W, Zhang S, Shan B … +9 more , Gu J, Xu F, Lu Y, Cang C, Li J, Han X, Cheng X, Dai Y, Zhang X
Exp Neurol · 2026 May · PMID 42219074 · Publisher ↗
Traumatic brain injury (TBI) is a life-threatening medical emergency that can induce a variety of neurological disorders. Circular RNAs (circRNAs) play critical roles in neural development, maintenance of homeostasis, an...
Traumatic brain injury (TBI) is a life-threatening medical emergency that can induce a variety of neurological disorders. Circular RNAs (circRNAs) play critical roles in neural development, maintenance of homeostasis, and the pathogenesis of neurological disorders. Nevertheless, the precise role of circRNAs in TBI remains unclear. In this study, we found that the expression level of circular RNA Crebrf (circCrebrf) was significantly downregulated in the cerebral cortex of rats following traumatic brain injury (TBI), and it was abundantly expressed in neurons. Furthermore, overexpression of circCrebrf could significantly ameliorate TBI-induced neurological deficits, cognitive impairment and neuronal apoptosis. Mechanistic investigations revealed that circCrebrf acted as a molecular sponge by specifically adsorbing miR-3562, thereby upregulating endoplasmic reticulum lipid-anchoring protein 1 (ERLIN1) expression. In turn, the upregulation of ERLIN1 effectively ameliorated mitochondrial dysfunction and suppressed cell apoptosis. Taken together, circCrebrf exerts a neuroprotective effect by regulating the miR-3562/ERLIN1 axis, thus alleviating secondary neurological injury following TBI. Therefore, circCrebrf is a promising novel potential therapeutic target for TBI intervention.
Corrigendum to "Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid β-peptide and the membrane lipid peroxidation product 4-hydroxynonenal" [Experimental Neurology, vol. 213,1 (2008): 114-21].
Tang SC, Lathia JD, Selvaraj PK … +7 more , Jo DG, Mughal MR, Cheng A, Siler DA, Markesbery WR, Arumugam TV, Mattson MP
Exp Neurol · 2026 Sep · PMID 42218080 · Publisher ↗
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Retraction Notice to "Endoplasmic Reticulum Stress Plays Critical Role in Brain Damage after Chronic Intermittent Hypoxia in Growing Rats" [Experimental Neurology 257 (2014) 148-156].
Cai XH, Li XC, Jin SW … +7 more , Liang DS, Wen ZW, Cao HC, Mei HF, Wu Y, Lin ZD, Wang LX
Exp Neurol · 2026 Sep · PMID 42218079 · Publisher ↗
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