Search Results (2,352)

Glutamate excitotoxicity is a critical pathological mechanism underlying neuronal death in ischemic stroke, epilepsy, and neurodegenerative diseases. Caveolin-1 (Cav-1), a structural protein of caveolae membrane microdomains, has emerged as a potential modulator of neuronal survival, yet its precise mechanisms in excitotoxicity remain incompletely understood. In this study, we investigated the role of Cav-1 in regulating glutamate-induced calcium dysregulation, reactive oxygen species (ROS) generation, and mitochondrial dysfunction in primary hippocampal neurons. Using Cav-1 overexpression (Cav-1OE) and Cav-1 knockdown (Cav-1KD) approaches, we demonstrate that Cav-1OE significantly attenuates glutamate-stimulated intracellular Ca²⁺ elevation, reduces ROS generation, and prevents mitochondrial membrane potential (Ψ_m) depolarization. Further investigation revealed that Cav-1OE reduces, while Cav-1KD enhances, calcium responses mediated by NMDA, AMPA, and KA receptors. These findings establish that Cav-1 functionally attenuates excitotoxic signaling by negatively regulating ionotropic glutamate receptor-mediated Ca²⁺ influx. Full article

Alzheimer’s disease and related dementias (ADRD) are neurodegenerative conditions characterized by progressive cognitive and functional decline. AD pathology is associated with extracellular amyloid-β plaques, intracellular tau neurofibrillary tangles, synaptic dysfunction, and neuronal loss. AD accounts for approximately 60–80% of dementia cases globally. In 2022, AD was the seventh leading cause of death in the United States, and the number of Americans aged 65 and older living with Alzheimer’s dementia is projected to increase substantially by 2060. Despite decades of research, AD/ADRD data resources remain fragmented across clinical, imaging, genetic, genomic, and therapeutic domains. This paper addresses that gap by providing a centralized review of widely used AD/ADRD databases and computational methods. We first summarize computational approaches used to analyze these datasets, including machine learning (ML), natural language processing (NLP), and biomedical imaging. We then review eight databases classified into three categories: Clinical and Population Data, Genetics and Genomics, and Drug Discovery and Therapeutics. Finally, we discuss real-world applications, including early diagnosis, clinical decision support, personalized medicine, and drug-mechanism analysis. This review identifies opportunities for future work in data harmonization, cross-database compatibility, and robust, generalizable AI models for AD/ADRD research. Full article

Accumulation of aggregated amyloid beta (Aβ) species is a defining pathological hallmark of Alzheimer’s disease and is associated with extensive neuronal structural abnormalities. Mild cognitive impairment (MCI), a transitional stage between normal aging and the onset of dementia, is thought to represent an early phase of this pathological continuum. Studies at the cellular level suggest that the conditions impair the maintenance of established neuronal processes/networks and restrict their capacity for elongation or re-elongation. They may also attenuate the activation and process extension of quiescent neural progenitor or stem-like cells. These early cellular changes precede overt neurodegeneration in neural tissue and are likely to contribute to cognitive decline. They highlight the importance of in vitro models for identifying molecular targets involved in recovery from disease. In this study, we investigated the effects of aggregated Aβ (25–35) on neuronal process elongation and associated intracellular events in the N1E-115 cell line, a widely used model of neuronal differentiation. Addition of aggregated Aβ to cultured N1E-115 cells attenuated process elongation in a concentration-dependent manner. This morphological impairment was accompanied by decreased expression of neuronal differentiation markers. In contrast, at the half-maximal inhibitory concentration for process elongation, long-term cultured cells did not exhibit apparent process retraction or degenerative morphology. This mild but progressive impairment, without extensive cell death, is consistent with the cellular features of early-stage conditions rather than advanced Alzheimer’s pathologies. Similar results were observed in primary cortical neurons. Aβ also decreased the level of GTP-bound Ras and phosphorylation of the downstream mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). Furthermore, treatment with hesperetin, a bioactive flavonoid compound, recovered the Aβ-induced inhibition of neuronal process elongation. Hesperetin also restored Ras and MAPK/ERK states, suggesting that its effects are associated, at least in part, with modulation of signaling through Ras and MAPK/ERK. Our findings suggest that hesperetin may serve as a useful molecular probe for modulating early cellular responses associated with Alzheimer’s disease-related pathology. This in vitro model might serve as a useful platform for investigating the molecular target candidates involved in recovery from nervous system disorders. Full article

Neonatal hyperoxia induces oxidative stress that disrupts neurodevelopmental processes. While dexmedetomidine (DEX) exhibits acute neuroprotective properties, its long-term impact on developmental trajectories during recovery remains incompletely understood. This study examined whether a single neonatal dose of DEX modulates hippocampal neurogenesis following hyperoxia across defined postnatal stages. Six-day-old Wistar rats were exposed to 80% oxygen for 24 h and evaluated at postnatal days (P) 9, 11, and 14 after recovery in room air. Mechanistically, hyperoxia permanently triggered apoptotic cascades, evidenced by sustained transcript upregulation and increased histological apoptosis and cell loss across the cortex and hippocampus, while disrupting the hippocampal progenitor niche, suppressing key differentiation factors (Sox2, Tbr2, Prox1, Calb1) and altering mature NeuN expression. Likewise, markers for autophagy (Atg5/12, Beclin1), neurotrophins (BDNF, NGF, NT3), and plasticity markers (Nrp1, Sem3a) showed reduced expression. Proactive treatment with DEX (5 µg/kg) significantly reversed these detrimental patterns. First, DEX elicited a robust antioxidant response (Nrf2, SOD1, SOD3 induction). Second, DEX effectively suppressed hyperoxia-induced programmed cell death and tissue degeneration up to P14. Crucially, this dual protection sustained the neurogenic niche, safeguarding autophagy processes as well as neurotrophic and neuronal plasticity mediators, while showing excellent safety under normoxia. In conclusion, a single dose of DEX mitigates acute oxygen injury and exhibits beneficial, stage-specific effects within hippocampal neurogenic niches during the postnatal phase, highlighting its potential to preserve neurodevelopmental trajectories. Full article

Background/Objectives: Serum neuron-specific enolase (NSE) is a biomarker of neuronal injury, but its prognostic role in pediatric convulsive status epilepticus (CSE) remains uncertain. We evaluated the association between serum NSE levels and short-term neurological outcome, assessed model calibration with internal bootstrap validation, and examined whether NSE provides incremental discrimination beyond established clinical severity scores. Methods: This was a single-center retrospective cohort study of children aged 1 month to 18 years admitted to a tertiary pediatric intensive care unit (PICU) with CSE as the primary admission diagnosis between January 2024 and November 2025. The primary outcome was poor neurological outcome at hospital discharge, defined as a worsening of ≥1 point in the Pediatric Cerebral Performance Category (PCPC) score from baseline (ΔPCPC ≥ 1) or in-hospital death. A multivariable logistic regression model adjusting for NSE, PRISM III, acute symptomatic etiology, and mechanical ventilation was developed, with bootstrap optimism-corrected internal validation (2000 resamples) and formal calibration assessment. Separate models for in-hospital mortality and for neurological deterioration among survivors were conducted as secondary analyses. Diagnostic operating characteristics were reported with 95% Wilson confidence intervals. The study followed the STROBE and TRIPOD reporting guidelines. Results: Of 132 children included (median age 26 months, 56.1% male), 60 (45.5%) had a poor neurological outcome including 18 deaths (13.6%). Serum NSE was significantly higher in the poor-outcome group (median 22.0 vs. 14.4 μg/L; p < 0.001). In the primary multivariable model, NSE (adjusted OR 1.11 per μg/L; 95% CI 1.06–1.19; p = 0.001) and PRISM III (adjusted OR 1.15; 95% CI 1.03–1.37; p = 0.013) were independently associated with poor outcome. The model showed acceptable calibration (Hosmer–Lemeshow p = 0.130) and a bootstrap optimism-corrected AUC of 0.759. NSE remained independently associated with both in-hospital mortality (aOR 1.13) and with ΔPCPC ≥ 1 in survivors (aOR 1.09). The AUC for NSE alone was 0.741 (95% CI 0.65–0.82) for poor outcome and 0.885 (0.79–0.96) for mortality. The combined PRISM III + NSE model showed a numerically higher but not statistically significant AUC compared with PRISM III alone (0.784 vs. 0.726; DeLong p = 0.103). Conclusions: Higher serum NSE is independently associated with adverse short-term neurological outcome and mortality in pediatric CSE, including in survivor-only analysis. However, the present data do not demonstrate clinically meaningful incremental prognostic value beyond PRISM III, and the proposed cutoff was derived and tested in the same cohort and is therefore optimistic. These findings are hypothesis-generating and require external validation in prospective multicenter cohorts with serial sampling and long-term neurodevelopmental follow-up before routine clinical use can be advocated. Full article

Hypoxic–ischemic brain injury remains the leading cause of death and neurological disability after cardiac arrest. Although targeted temperature management (TTM) and other neuroprotective strategies have demonstrated promising results in preclinical studies, large randomized controlled trials have largely failed to show consistent clinical benefit. This review examines two major limitations that may contribute to these translational failures: delayed initiation of therapy beyond a time-limited therapeutic window and the lack of baseline injury severity stratification. Evidence from both experimental and clinical studies suggests that the opportunity to modify neurological injury may be confined to the first few hours after return of spontaneous circulation (ROSC). Delayed intervention may occur after irreversible neuronal injury, microvascular dysfunction, and impaired cerebrovascular autoregulation have already become established. In addition, cardiac arrest survivors represent a heterogeneous population. Patients with minimal injury may recover with standard supportive care, whereas those with severe irreversible injury are unlikely to benefit from neuroprotective interventions. Patients with moderate-severity brain injury may represent the subgroup most likely to respond to targeted therapies. Ultra-early stratification using neuroimaging, electroencephalography, circulating biomarkers, and clinical risk scores may help identify patients with therapeutic potential. This review proposes that future post-cardiac arrest research should integrate both time-sensitive intervention strategies and early injury severity stratification. Large prospective studies and randomized controlled trials are needed to determine not only whether interventions are effective, but also when they should be initiated and which patients are most likely to benefit. Full article

Aminochrome, an endogenous neurotoxin, has been implicated in the loss of neuromelanin-containing dopaminergic neurons in the nigrostriatal system in Parkinson’s disease. Although aminochrome-induced oxidative stress and its inhibitory effects on microtubule polymerization are well documented, its impact on protein aggregation remains poorly understood. The aim of this research was to evaluate the effects of aminochrome on protein aggregate accumulation in SH-SY5Y cells differentiated into dopaminergic neurons. While the role of aminochrome in autophagy has been described, its direct effect on autophagosome–lysosome fusion has not been studied. Our findings reveal that aminochrome, like vinblastine, delays autophagosome–lysosome fusion and induces cell death. This inhibitory effect was also observed in the presence of autophagy inducers, which partially attenuated aminochrome-induced cell death. Under these conditions of disruptions in autophagosome–lysosome fusion, a marked accumulation of perinuclear vimentin and ubiquitin aggregates was observed. Aminochrome also increased colocalization between vimentin and ubiquitin. Interestingly, ubiquitin aggregates were also detected within the nucleus. These findings suggest that aminochrome-induced disruption of the microtubule network, particularly its impairment of autophagosome–lysosome fusion and promotion of protein aggregation, may represent a critical mechanism leading to cell death. In addition, inhibition of autophagosome–lysosome fusion may contribute to the accumulation of perinuclear and nuclear protein aggregates, which may be associated with either toxic or non-toxic pathways. Our findings underscore the therapeutic potential of targeting both microtubule stabilization and proteostasis pathways, including autophagy and the ubiquitin–proteasome system (UPS), in Parkinson’s disease, highlighting the need for further research into nuclear proteotoxicity mechanisms. Full article

Neurodegenerative diseases are increasingly recognized as disorders of due to disrupted cellular homeostasis, with mitochondrial dysfunction playing a central and early role in disease progression. This review explores the intricate relationship between mitochondrial function and neuronal health, emphasizing the pivotal role of the solute carrier family 25 (SLC25) transporters in maintaining mitochondrial homeostasis. We provide a comprehensive overview of mitochondrial biology in the central nervous system, including energy metabolism, calcium signaling, redox regulation, organelle interactions and mitochondrial dynamics. We delve into the SLC25 transporter family, highlighting their transport mechanisms, substrates and roles in brain metabolism and neuroprotection. SLC25 on one hand and proteins involved in the regulation of mitochondrial morphology and calcium signaling on the other hand are two sides of the same coin influencing each other. A critical analysis follows, examining how mitochondrial dysfunction contributes to mitochondrial abnormalities in a spectrum of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, ALS and rare mitochondrial encephalopathies. Finally, we assess emerging therapeutic strategies targeting mitochondrial pathways and SLC25 function, including metabolic modulation, gene therapies, antioxidants and pharmacological agents. This review underscores mitochondria and the SLC25 transporters as promising targets for disease-modifying interventions in neurodegeneration and raises key questions about the causality between mitochondrial failure and neuronal death. Full article

Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive sphingolipid that regulates key cellular processes, like proliferation, apoptosis, inflammation, and vascular homeostasis. S1P acts as a signaling molecule both inside and outside cells by interacting with five G-protein-coupled S1P receptors (S1PR1–S1PR5). Accumulating evidence indicates that dysregulation of S1P signaling is implicated in the pathophysiology of cerebral ischemia/reperfusion (I/R) injury and Alzheimer’s disease (AD). In I/R injury, S1P signaling regulates vascular permeability, immune cell infiltration, and neuronal survival and death. In AD, alterations in S1P metabolism are associated with β-amyloid deposition, tau hyperphosphorylation, synaptic dysfunction, and sustained neuroinflammation. S1P receptor (S1PR) modulators represent promising therapeutic agents in both preclinical and clinical studies. Fingolimod was the first oral disease-modifying therapy approved for the treatment of multiple sclerosis and, at the same time, the first S1PR modulator introduced into clinical practice. New selective S1PR-targeting agents, including siponimod and ozanimod (S1PR1 and S1PR5), as well as the S1PR1-selective agent ponesimod, have also been approved for clinical use. In addition to their immunomodulatory properties, S1PR modulators have direct effects in the central nervous system, facilitating the maintenance of blood–brain barrier integrity, reducing microglial activation, and enhancing neuronal survival pathways. Building on this knowledge, we discuss the role of S1P signaling, highlighting recent advances in S1PR modulators as promising therapeutic agents for cerebral I/R injury and AD. Full article

Background/Objectives: Stroke remains the second leading cause of death worldwide, and cell therapy is among the most actively investigated strategies for its treatment. Recent transcriptomic evidence has revealed that 293T cells—the most widely used transient transfection model—possess a neural crest/neuronal lineage, making them a candidate for acute neural tissue engineering. Methods: We implanted iron oxide nanoparticle-labeled 293T cells (293T-ION) into an ischemic rat brain and monitored them longitudinally by 7T MRI, using ION-labeled bone marrow-derived mesenchymal stem cells (rMSC-ION) as a direct comparison. Functional recovery was assessed via mNSS and corner test scores, and infarct size was quantified by MRI. Results: 293T-ION cells showed no migration throughout the 40-day observation period, and functional recovery plateaued early compared with the progressive improvement seen with rMSC-ION. 293T cell implantation provoked pronounced, localized CD68-positive microglial hyperactivation at both implantation and ischemic sites, without migration toward the choroid plexus (CP). In contrast, rMSC-ION actively migrated to the CP and drove superior neuroplasticity marker expression (Ki67, Nestin, NeuN). Conclusions: 293T cells produce transient localized microglial activation and limited brain plasticity, whereas rMSCs drive sustained neurorestoration. Synergistic co-administration of these cell types may represent a future therapeutic strategy bridging hyper-acute and chronic recovery phases. Full article

Osteoarthritis (OA) and major depressive disorder (MDD) share inflammatory and oxidative stress pathways, but the role of programmed cell death (PCD) in their comorbidity remains unclear. This study used independent OA synovial and MDD peripheral blood transcriptomic datasets—not a unified comorbid discovery cohort—to identify candidate PCD-related molecular signatures commonly dysregulated in both conditions. Transcriptomic data from OA synovium and MDD brain tissues were obtained from GEO (six training [three OA synovial and three MDD peripheral-blood], seven validation, and two single-cell RNA-seq datasets). Differentially expressed genes (DEGs) were identified, and PCD-related DEGs were screened. Machine learning (LASSO, SVM-RFE, Random Forest) was used to identify hub PCD-DEGs from the OA training set. WGCNA identified MDD-associated modules for comorbidity-gene selection. Functional enrichment, immune infiltration, scRNA-seq localization, and clinical validation (qRT-PCR/WB) were performed. From the OA cohort, four hub PCD-DEGs (CDKN1A, CX3CR1, INHBB, RHOB) showed moderate diagnostic value for OA (nomogram AUC = 0.82). Eight candidate genes (VAMP8, PDK4, P2RX4, ITM2C, IL10RA, HSP90AA1, CTSO, CRIP1) were commonly dysregulated across both OA and MDD datasets. Immune infiltration revealed upregulated B memory cells, plasma cells, Tregs, and neutrophils in OA, and neutrophils in MDD. scRNA-seq localized CDKN1A/RHOB to OA synovial cells and HSP90AA1/ITM2C to MDD neurons. Enrichment analyses highlighted TNF signaling, apoptosis, and stress responses in both diseases. An independent OA–MDD clinical cohort confirmed differential expression of CDKN1A, RHOB, ITM2C, and HSP90AA1. This study identifies four PCD-related hub genes associated with OA and eight candidate comorbidity genes showing common dysregulation across OA and MDD datasets and in an independent clinical cohort. These findings generate hypotheses about shared inflammatory pathways linking OA and MDD. As these associations derive from independent disease-specific cohorts rather than a true comorbid discovery cohort, they represent candidate signatures requiring functional validation rather than established mechanisms. Full article

Background/Objectives: Alzheimer’s disease (AD) is characterized by beta-amyloid (Aβ) plaque deposition, which impairs several cellular processes, including autophagy. Considering the multifactorial nature of AD, the development of therapies acting on alternative molecular targets is necessary. In this study, we evaluated the neuroprotective effect of a molecule from the hydrozoan Eudendrium carneum and investigated its impact on autophagy-related pathways. Methods: The secretion of E. carneum was fractionated by RP-HPLC according to its neuroprotective activity in SH-SY5Y cells exposed to oAβ42, evaluated using LDH and MTT assays. The purified molecule (named EC5), characterized by mass spectrometry, was evaluated regarding in silico toxicity and calcium dynamics. Neuronal lysosomal morphology was assessed using the LysoTracker probe, and cathepsin D activity was determined using a synthetic substrate. The expression of autophagy-related proteins (mTOR, LAMP-1, and LC3B) was evaluated by dot blotting, and amyloid plaque clearance was quantified using Thioflavin-T staining. Results: The steroid glycoside putatively identified as Sarmentoside B (EC5) exhibited neuroprotective effects and showed no toxicity or alterations in neuronal calcium or sodium channel dynamics. EC5 restored lysosomal morphology and cathepsin D activity, reversing the impairment induced by oAβ42. Furthermore, EC5 reduced mTOR expression, and this interaction was supported by molecular docking analysis. Lysosomal restoration promoted the clearance of oAβ42 aggregates, as evidenced by Thioflavin-T staining, resulting in reduced neuronal death. Conclusions: EC5, putatively identified as Sarmentoside B, exerts neuroprotective effects against oAβ42-induced toxicity by promoting autophagy-related amyloid clearance, highlighting its therapeutic potential for AD. Full article

Central nervous system oxygen toxicity (CNS-OT) is a major complication of hyperbaric oxygen (HBO) characterized by seizures and neuronal damage, yet the underlying mechanisms remain incompletely understood. Using male Sprague Dawley rats (n = 6 per group) and HT22 neurons exposed to either HBO (6 ATA, 100% O₂) or hyperbaric normoxia (HNO), our results demonstrate that HBO, but not HNO, caused mitochondrial structural damage and loss of mitochondrial membrane potential (ΔΨm). Transcriptomic analysis revealed enrichment of apoptosis and mitogen-activated protein kinase (MAPK) signaling pathways. Using HeLa cells stably overexpressing Parkin and Mito-Keima, a pH-sensitive mitochondrial probe system for monitoring mitophagy, we observed that mitophagic flux was initiated but proceeded too slowly to clear damaged mitochondria in a timely manner in HBO-exposed neurons. Pharmacological preconditioning to activate mitophagy enabled the prompt elimination of dysfunctional mitochondria and rescued HBO-induced mitochondrial dysfunction and cell death. In vivo, everolimus treatment promoted timely mitophagic clearance, prolonged seizure latency, attenuated ΔΨm loss, and suppressed p-p38 activation. These findings demonstrate that HBO exposure disrupts mitochondrial homeostasis and activates pro-apoptotic MAPK signaling. Meanwhile, endogenous mitophagy is initiated but fails to clear damaged mitochondria in a timely manner. Pre-activation of mitophagy by everolimus enables the timely clearance of damaged mitochondria, protecting against CNS-OT and highlighting a promising therapeutic strategy. Full article

The ketogenic diet, a high-fat and low-carbohydrate diet, has potential therapeutic effects on various neurological and psychiatric disorders. The diet shifts the body’s energy production in the form of adenosine triphosphate from using glucose to fats. The increased fatty acid β-oxidation results in the production of ketone bodies. This metabolic adaptation changes cellular bioenergetics, especially in the brain, which is highly reliant on energy metabolism. Schizophrenia, a psychotic disorder, and bipolar disorder, a mood disorder, are distinct psychiatric illnesses that can both involve disturbances in mood, cognition, and perception. These disturbances differ in prominence and clinical significance between the two conditions. Although the underlying mechanisms behind each disorder vary, they share some common pathophysiology, such as imbalances in the neurotransmitter system, mitochondrial dysfunction, and oxidative stress. Alzheimer’s disease, a neurodegenerative disorder marked by progressive cognitive decline, shares similar cellular disruptions, along with additional pathological features such as neuroinflammation and neuronal death. Recent studies suggest that the ketogenic diet may exert therapeutic effects by modulating underlying biochemical pathways. Its ability to reduce oxidative stress, improve mitochondrial function, and stabilize neurotransmitter balance may help alleviate symptoms and potentially slow disease progression. Full article

Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by progressive cognitive decline due to the loss of neurons. The accumulation of extracellular senile plaques (Aβ) and intracellular tau neurofibrillary tangles (NFTs) is a key pathological feature of AD. Mitochondrial dysfunction is implicated in all key AD pathologies, whether as a cause or a consequence of disease progression. Growing evidence indicates that mitochondrial impairment plays a central role in AD pathogenesis by disrupting cellular homeostasis, promoting oxidative stress, and contributing to progressive neuronal death. Therefore, targeting mitochondria may offer promising insights into the development of disease-modifying therapies. In this review, we summarize current evidence on the role of mitochondrial dysfunction in the pathophysiology of AD and on its therapeutic potential. Full article