Cellular and Molecular Neurobiology最新文献

Ischemic stroke, a leading cause of disability and mortality, initiates a complex damage cascade within the neurovascular unit (NVU), leading to blood-brain barrier (BBB) disruption and neuroinflammation that severely exacerbates secondary injury. Neuroglobin (Ngb), an endogenous protein induced by brain injury, represents a high-potential neuroprotective target. While the precise mechanisms underlying its protective action remain incompletely elucidated, substantial evidence points to its multifaceted ability to mitigate ischemic damage. To fully unlock this potential, a fundamental understanding of how neurons, astrocytes, microglia, and pericytes, coordinate their function in response to stress, and specifically identifying the role Ngb plays within this integrated cellular network, is required. This review examines the post-stroke interplay among these cells, analyzing current knowledge about how Ngb modulates the collective inflammatory response by suppressing pro-inflammatory pathways and fostering a neuroprotective environment. Furthermore, Ngb's upregulation in glial cells and pericytes promotes direct neuronal repair mechanisms, such as neurite outgrowth and axonal regeneration, while supporting neuronal survival and BBB integrity. Importantly, evidence suggests that Ngb's efficacy is most pronounced when its intracellular concentration exceeds the levels achieved through physiological upregulation. In this regard, we integrate broad preclinical evidence with specific insights from nanoparticle-mediated delivery systems that enable effective Ngb transport to NVU cells. These synthesized findings demonstrate beneficial outcomes in stroke models, driven by the modulation of mitochondrial dynamics, cytoskeletal remodeling, and synaptic regeneration pathways. Collectively, the literature indicates that targeted therapeutic Ngb may enhancement strategies effectively complement endogenous levels to orchestrate protective responses across the NVU. Nonetheless, a detailed investigation into the therapeutic utility of Ngb is still required to fully translate encouraging preclinical findings into successful clinical application for improving stroke outcomes.

Neuro-inflammation is implicated in the onset of neuropathologies and can be promoted by stroke, trauma, toxins or infections. Brain tissue is rich in Tissue factor (TF) which is also released within cerebrospinal fluid as extracellular vesicles (EV). TF is an inflammatory protein which is increased during chronic conditions, and initiates blood coagulation and promotes tissue repair. This study examined the influence of TF on the expression, phosphorylation, aggregation and degradation of Tau protein in differentiated human cells SH-SY5Y and HCN-2, and rat neuronal cells. Studies were performed using vesicles containing TF or recombinant TF supplemented with factor VIIa (fVIIa) and also in the presence of various reagents and antibodies. Treatment of the differentiated cells with TF or TF-EV, upregulated the expression of Tau mRNA and protein, and was enhanced on repeated treatment. Incubation of cells with TF-fVIIa increased Tau expression and resulted in significant phosphorylation at Thr181, and was less at Ser202. Inhibition of the protease activity of TF-fVIIa, or blocking PAR2 activation on cells using SAM11 antibody, reduced Tau phosphorylation at Thr181. Examination of the Tau protein at intervals post-treatment indicated that Thr181 phosphorylation was present in bands of approximately 50 and 30-35 kDa while phosphorylation of Ser202 was associated with a 43 kDa band. Exposure of the cells to TF alone was sufficient to induce PKC-dependent phosphorylation of Tau. Prolonged treatment of differentiated SH-SY5Y cells with TF, resulted in higher staining with Amytracker dye. Finally, controlled digestion of recombinant full-length Tau with TF-fVIIa resulted in a smaller fragment. In conclusion, our data presents potential mechanisms by which TF influences Tau metabolism in neurons, being both beneficial in terms of clearance and regeneration, and having detrimental outcomes including aggregation.

Perioperative neurocognitive disorder (PND) is a common complication following thoracic surgery and often leading to poor outcomes. Despite ongoing research, effective treatments for late PND remain limited. Identifying reliable biomarkers for early diagnosis is, therefore, essential. A prospective cohort study was conducted with 60 elderly patients undergoing thoracic surgery. Serum samples were collected within 10 minutes prior to anesthesia and following extubation to measure adiponectin (APN), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), aquaporin-4 (AQP4) and brain-derived neurotrophic factor (BDNF). Among PND patients, serum APN, PKA, AQP4, and BDNF levels were markedly decreased compared with the normal group. While serum cAMP (HR = 1.087, p = 0.695, 95% CI [0.284-4.166]) and PKA (HR = 0.996, p = 0.09, 95% CI [0.491-0.947]) were not significantly correlated with PND, serum APN (HR = 0.307, 95% CI [0.113-0.835], p = 0.021), AQP4 (HR = 0.204, 95% CI [0.060-0.697], p = 0.011), and BDNF (HR = 0.382, 95% CI [0.177-0.823], p = 0.014) were protective factors against PND. ROC analysis demonstrated that APN (AUC = 0.68, 95% CI [0.51-0.87]), AQP4 (AUC = 0.73, 95% CI [0.59-0.87]), BDNF (AUC = 0.73, 95% CI [0.59-0.87]), and the model of combining those biomarkers (AUC = 0.91, 95% CI [0.83-0.99]) could predict PND. PND patients exhibited a lower protective stress response to surgical trauma. High serum APN, AQP4, and BDNF levels were independent protective factors for PND, and a combined model of these biomarkers showed predictive potential for PND.

Peripheral nerve injuries (PNIs) remain a major cause of long-term disability, with standard treatments such as microsurgical repair and autologous grafting often yielding incomplete recovery due to slow axonal regeneration, fibrotic scarring, and limited reinnervation. Emerging therapies, including electrical stimulation (ES) and platelet-rich plasma (PRP), have shown promise but remain insufficient as standalone interventions. ES enhances axonal elongation, remyelination, and neuroplasticity by upregulating regeneration-associated genes and neurotrophins, while PRP delivers autologous growth factors that promote angiogenesis, Schwann cell activation, immunomodulation, and antioxidant defense. Both therapies converge on shared pathways by reducing inflammation, oxidative stress, and scar formation, thereby remodeling the microenvironment into a pro-regenerative niche. Preclinical evidence indicates that combining ES and PRP provides complementary benefits, with ES priming the injury site and PRP sustaining trophic support, resulting in superior axonal density, myelination, and functional recovery compared to monotherapies. Future directions emphasize personalized protocols, optimized ES parameters, standardized PRP formulations, and integration with biomaterials and closed-loop stimulation systems. Translation to clinical practice, however, requires standardized guidelines and rigorous randomized controlled trials to validate these multimodal strategies and enable patient-specific regenerative therapies.

Glioblastoma is a lethal primary brain tumor with poor prognosis. Tumor cells exhibit substantial phenotypic variation, complicating treatment. As functional diversity is driven by underlying transcriptional states, characterizing tumor cell gene expression is essential for understanding tumor biology and therapeutic response. The GL261 tumor cell line is a common pre-clinical model system for investigating glioblastoma pathobiology. However, global gene expression patterns in this model are unknown. Here we describe the use of single-cell RNA sequencing (scRNA-Seq) to investigate transcriptional profiles of 5764 adherent and 4951 neurosphere GL261 cells, generating 133,442,221 sequenced reads. Following Principal Component Analysis (PCA) for dimensionality reduction, we applied Uniform Manifold Approximation and Projection (UMAP) to visualize transcriptionally distinct subpopulations (clusters) of GL261 cells grown adherently or as neurospheres. Highly expressed and differentially expressed genes were identified. Because the neurosphere phenotype is known to be more tumorigenic, we further examined differentially expressed genes with gene ontology expression analysis. We found that upregulated genes in neurosphere cells are associated with angiogenesis, cell adhesion, and cell signaling pathways. In addition, we specifically examined gene expression patterns of matrix metalloproteinases and purinergic receptors, glioblastoma drug targets known to be important for promoting tumor infiltration into adjacent healthy tissue. We found that P2RX7, MMP15 and MMP16 are upregulated in neurosphere cells, indicating a potential role for these genes in tumor formation. Together these results reveal global transcriptional profiles of GL261 cells, establish a resource for further scRNA-Seq-based analyses, and give insight into gene expression changes relevant to glioblastoma tumor development.

Lesch-Nyhan disease (LND) is an ultra-rare X-linked inborn error of metabolism caused by complete or partial deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), a key enzyme in the purine salvage pathway. This defect leads to uric acid overproduction and a broad spectrum of neurological and behavioral manifestations, whose severity depends on the degree of residual enzymatic activity. Although emerging evidence implicates HPRT deficiency in widespread cellular dysfunctions, particularly within midbrain dopaminergic neurons, the molecular mechanisms underlying the neurobehavioral phenotype of HPRT deficiency remain poorly understood and are not adequately explained by purine metabolism dysfunctions alone. Although proteomics represents a powerful approach for elucidating molecular alterations underlying disease, it has so far found only limited application in LND research. To address this gap, we provide here the first proteomic study combined with clinical biochemistry data and pro-inflammatory cytokines profiling of plasma samples from 29 HPRT deficient individuals (21 with classic LND and 8 with Lesch-Nyhan variants - LNV). We suggest that plasma proteomics might be a potential tool in LND for monitoring disease progression and therapeutic response, potentially paving the way for targeted treatment strategies that extend beyond the purine salvage pathway to address the currently unmet clinical needs of LND patients.

Alzheimer's disease (AD) is a neurodegenerative disease closely associated with age. The main clinical manifestations include cognitive impairment, including visuospatial ability, memory, language, and behavioral disorders. These manifestations considerably impair the patients' ability to perform daily activities. Although the pathogenesis of AD remains unclear, many studies have confirmed the essential role of abnormal lipid metabolism and inflammatory response in AD occurrence and progression. In this review, based on the relationship between lipid metabolism disorders and neuroinflammation, the regulatory mechanism of lipid mediators, and the role of microglia, we systematically discuss how lipid metabolism affects the pathological process of AD by regulating the inflammatory response.