Journal of Molecular Neuroscience最新文献

Although multi-omics studies have increasingly revealed molecular alterations associated with epilepsy, clinically accessible cerebrospinal fluid (CSF) biomarkers that are stably detectable and biologically relevant remain scarce. This study aimed to identify measurable biomarkers associated with epilepsy-related molecular alterations. Kainic acid (KA)-induced mouse model, single-cell RNA sequencing, and public transcriptomic datasets identified secreted protein-coding genes associated with inflammation, glial activation, and metabolic dysregulation. Candidate biomarkers were validated across mouse and human datasets and quantified in CSF of patients with temporal lobe epilepsy (TLE) and non-epileptic controls using enzyme-linked immunosorbent assays. Machine learning models were built to evaluate diagnostic performance and interpretability using SHAP analysis. Six proteins (C-X-C motif chemokine ligand 10 [CXCL10], transthyretin [TTR], apolipoprotein E [APOE], apolipoprotein D [APOD], galectin-3-binding protein [LGALS3BP], and lysozyme [LYZ]) were dysregulated in human CSF. CSF levels of CXCL10, APOE, APOD, LGALS3BP, and LYZ were significantly elevated in TLE, whereas TTR was markedly reduced (all p < 0.001). Machine learning models demonstrated promising classification performance, with TTR and CXCL10 emerging as major contributing features. CSF CXCL10 levels positively correlated with preoperative seizure frequency (Spearman’s ρ = 0.698, p < 0.0001). Multilevel evidence from animal models and clinical CSF samples indicates that microglial activation and glia-related molecular alterations are associated with TLE progression, and related secreted proteins may provide candidate biomarkers for future translational investigation.

Post-stroke cognitive impairment (PSCI) markedly impairs rehabilitation efficacy and quality of life. Safe and effective interventions are urgently needed. Eighty-four patients with PSCI were randomly allocated into three groups (n = 28 per group). Group A received conventional cognitive training. Group B received conventional training plus scalp acupuncture. Group C received the treatment of Group B combined with mouse nerve growth factor (mNGF) acupoint injection. All interventions lasted 4 weeks. All groups exhibited significant within-group improvements in MoCA, ADL, MBI, and FMA scores after intervention. Group C achieved the optimal cognitive efficacy:​ the post-treatment MoCA score was 26.7 ± 2.9 (95% CI, 25.53–27.87), significantly higher than that in Group A (21.5 ± 3.5 (95% CI, 20.22–22.78), P < 0.001) and Group B (23.8 ± 3.2)(95% CI, 22.48–25.12), P = 0.003). The ADL score in Group C was the lowest among the three groups (F = 28.963, P < 0.001), suggesting better independence. Moreover, motor function (FMA) and basic self-care ability (MBI) were also significantly improved in all groups after intervention. There were significant inter-group differences in post-treatment FMA and MBI scores (F-FMA = 29.745, P < 0.001; F-MBI = 35.872, P < 0.001). The scores increased gradually from Group A to Group C, with Group C achieving the best improvement. Conventional cognitive training improves cognitive function and daily living ability in patients with PSCI. Scalp acupuncture combined with conventional training is more effective than training alone. The triple therapy of conventional training, scalp acupuncture, and mNGF acupoint injection further enhances rehabilitation outcomes, with prominent clinical application value.

Obstructive sleep apnea is characterized by recurrent intermittent hypoxia (IH), which contributes to neuroinflammation and neurological dysfunction. Microglia are pivotal regulators of inflammatory responses in the central nervous system, but the molecular mechanisms underlying IH-induced microglial activation remain unclear. This study aimed to identify key genes mediating this phenomenon and to elucidate their functional significance. An IH model was established in BV2 cells, with inflammation assessed via western blot for cyclooxygenase-2 (COX2) /inducible nitric oxide synthase (iNOS) and ELISA for Interleukin-6 (IL-6) /Tumour necrosis factor-alpha (TNF-α). RNA sequencing was performed to profile transcriptional changes induced by IH. Differential expression analysis, functional enrichment analysis, protein interaction network analysis, transcription factor prediction, and machine learning-based screening were integrated to identify candidate key genes. Pharmacological modulation of Nr1d1 was then performed to evaluate its role in IH-induced inflammation. IH significantly increased COX2, iNOS, IL-6 and TNF-α levels in BV2 cells. Transcriptomics showed distinct profiles between control and IH groups. Enrichment analyses linked IH-related genes to immune regulation, stress responses, and metabolic pathways. Network analysis highlighted a circadian gene cluster as a prominent component of the IH-responsive transcriptional network. Integrated network and machine learning analyses further identified Nr1d1 as a key candidate. Pharmacological experiments showed that inhibition of Nr1d1 attenuated IH-induced inflammatory responses. IH induces pronounced inflammatory activation and transcriptional reprogramming in BV2 cells. Nr1d1 may represent a circadian-associated candidate regulator involved in IH-induced microglial inflammatory activation.

Postoperative cognitive dysfunction (POCD) is a common complication of surgery in elderly patients and is characterized primarily by memory impairment; however, the underlying mechanisms remain incompletely understood. By utilizing a laparotomy model in aged mice and the delayed spatial alternation task (DSAT), we found that surgery specifically impaired the memory consolidation process. Importantly, this impairment was accompanied by significant disruption of sharp-wave ripples (SPW-R) in the hippocampal CA1 region. Previous research has indicated that trafficking of GluA2-containing AMPARs at CA3 recurrent synapses is crucial for SPW-R generation. Therefore, we examined postsynaptic AMPARs in the CA3 region after surgery and observed reduced membrane expression of GluA2-containing AMPARs, although the total protein levels and gene transcription remained unchanged. Immunofluorescence and coimmunoprecipitation revealed significantly decreased colocalization and binding of GluA2 with postsynaptic density protein 95 (PSD95), suggesting impaired synaptic GluA2 trafficking. Importantly, immediate postoperative injection of TAT-GluA2_3Y into the CA3 region to increase GluA2 synaptic expression significantly ameliorated surgery-induced SPW-R disruption and memory consolidation deficits. Conversely, local injection of a GluA2 cross-linking agent into the CA3 region of aged mice to inhibit GluA2 trafficking mimicked the postoperative phenotypes of SPW-R disruption and memory consolidation deficits. These results reveal that surgical trauma induces impaired GluA2 trafficking at hippocampal CA3, leading to CA1 SPW-R disruption and ultimately resulting in memory consolidation deficits. This discovery provides not only a novel molecular and neural circuit explanation for the pathogenesis of POCD but also an experimental foundation for the development of neuroprotective strategies targeting GluA2 trafficking.

Facioscapulohumeral muscular dystrophy(FSHD) is a genetic and heterogeneous neuromuscular disorder primarily driven by DUX4 derepression. The marked clinical variability observed among affected individuals suggests the presence of additional genetic modifiers, however underlying factors remain largely unclear. Investigating coincidental hereditary conditions within families may provide critical insights into such modifying mechanisms. We investigated a multigenerational family exhibiting the co-occurrence of FSHD and hereditary macrothrombocytopenia. Detailed neurological and hematological evaluations were performed across family members. Trio whole-exome sequencing(WES) was performed in selected individuals, followed by DNA sequencing and segregation analysis of identified genes. In silico structural analyses were performed for candidate variants. Candidate variants were additionally screened in an independent cohort with next generation sequencing. Clinical severity was assessed using the Clinical severity score(CSS), FSHD clinical score, and age-corrected CSS(ACSS). Trio-WES analysis identified a pathogenic frameshift mutation(c.1848delT) in GP1BA gene, responsible for macrothrombocytopenia. Among candidate variants located near GP1BA, a missense variant in MYH2(c.5045G > A) was prioritized due to its known association with myopathy and its involvement in DUX4-related pathways. Segregation analysis revealed that GP1BA mutations were present in five of nine FSHD-affected individuals, four of whom also harboured the MYH2 variant. Neither mutation was detected in unaffected family members. Individuals carrying the MYH2 variant consistently exhibited higher ACSS values compared to family members who did not carry the variant. Screening of MYH2 c.5045G > A (p.Arg1682His) and GP1BA c.1848delT variants in an independent cohort of 30 FSHD1 patients revealed no variant carriers, with all individuals exhibiting a wild-type genotype. Network analysis focusing on the interaction landscape between the FSHD key protein DUX4 and MYH2, using the Integrated Interactions Database(IID), revealed ACTN1 as a connecting node linking these pathways. Our findings suggest that rare MYH2 variants may act as a genetic modifier influencing the clinical severity in FSHD, which has not been previously reported. This study highlights the value of investigating co-occurring hereditary conditions to uncover novel molecular contributors to disease heterogeneity in FSHD. The potential role of MYH2 and its rare variants as genetic modifiers should be further validated in larger cohorts and functional studies.

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Human umbilical cord mesenchymal stem cells (hUCMSCs) have shown promise for treating ischemic stroke (IS) by promoting neural repair. The Notch signaling pathway is known to regulate neural stem cell (NSC) proliferation and differentiation, but its role in hUCMSC-mediated neuroprotection remains unclear. This study aimed to evaluate the therapeutic effects of hUMSCs in a mouse model of middle cerebral artery occlusion (MCAO) and investigate the involvement of the Notch pathway. Fifth generation of hUCMSCs were characterized by flow cytometry. In vitro, hUCMSCs were induced to differentiate with or without DAPT (a Notch inhibitor) or Jagged1 (a Notch agonist), and neural differentiation was assessed by Nestin and MAP2 expression. In vivo, MCAO mice received hUCMSC transplantation, and NSC proliferation, differentiation, and neural repair were evaluated using BrdU/Nestin immunofluorescence, qRT-PCR, Western blot, mNSS scoring, TTC, Nissl, and TUNEL assays. HUCMSCs displayed typical mesenchymal markers (CD90, CD44, CD105, and CD73) and low expression of hematopoietic markers. In vitro, DAPT enhanced hUCMSC differentiation into neuron-like cells, while JAG1 reversed this effect, confirming the mechanistic role of Notch signaling. In MCAO mice, hUCMSC transplantation promoted NSC proliferation and differentiation in the SVZ, reduced infarct volume and water content, increased Nissl-positive neurons, decreased apoptotic cells, and lowered mNSS scores. Inhibition of Notch signaling further augmented these therapeutic effects. HUCMSCs promote neural differentiation and neuroprotection in ischemic brains, at least in part by modulating the Notch signaling pathway. These findings highlight hUCMSCs as a promising therapeutic strategy for IS.

Focal demyelination refers to localized loss of myelin sheath that surrounds the nerve fibers. It impairs the efficient transmission of nerve impulses results in neurological symptoms. Here, our goal is to investigate the differential and combined effects of lysolecithin (LPC) and lipopolysaccharides (LPS) on brain and spinal cord demyelinating process. To confirm the pattern of demyelination, behavioural analysis was performed. Further, brain and spinal cord samples were collected at Day-post injection-1, 3, 7, and 28. The loss of axonal structures and neuronal bodies were assessed using Luxol fast blue and Nissl staining respectively. Immunofluorescence studies were done to examine demyelination and its impact on endothelial activation, astrogliosis, and activated microglia. Our data revealed that the combination group exhibited remarkable demyelination compared to the LPC and LPS groups alone. Additionally, endothelial activation, astrogliosis, and activated microglia were more pronounced in the combination group. Moreover, we found much of these effects were most pronounced in the spinal cord compared to corpus callosum, suggesting the presence of compensatory mechanisms and a unique brain microenvironment. This study is the first to demonstrate the synergistic effects of LPC and LPS toxins compared to their individual effects in both the brain and spinal cord.

While anti-amyloid immunotherapy has shown clinical benefit, amyloid-related imaging abnormalities (ARIA), comprising vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), represent the principal safety limitation. This paper presents a theoretical construct not yet based on empirical data. As a theoretical construct, we systematically synthesize current published findings on ARIA pathophysiology, plasma biomarker biology (glial fibrillary acidic protein [GFAP], amyloid-beta [Aβ] 42/40 ratio, neurofilament light chain [NfL], and phosphorylated tau [p-tau217]), and clinical trial outcomes. We propose that ARIA is fundamentally a kinetic—not static—pathological event, driven by the velocity of immune-mediated amyloid clearance. The Neuro-Pharmacological Kinetic Stress Test (NPKST) measures plasma biomarker velocity (rate of change per unit time) at Days 3–4 and 7 following the first therapeutic dose. A rapid spike in plasma GFAP velocity (ΔpGFAP/Δt), a precipitous decline in Aβ42/40 ratio velocity, and early NfL elevation constitute early biochemical signatures of individuals at high risk for clinically significant ARIA before macroscopic MRI changes are detectable. The Biomarker Velocity Composite Index (BVCI) stratifies patients into Low, Intermediate, and High Velocity tiers, each linked to specific dosing modification protocols. The cardiac stress test analogy provides the conceptual scaffold: the first therapeutic dose serves as the ‘pharmacological stress,’ and the BVCI captures the individual’s dynamic neuro-immune-vascular response phenotype. This proposed theoretical framework, if validated through future pilot studies and the KINETIC-ARIA trial, would shift ARIA prevention from reactive MRI surveillance to proactive biomarker-guided risk management. Long-term monitoring of potential ARIA effects is warranted.

Parkinson’s disease (PD) and Alzheimer’s disease (AD) are both neurodegenerative disorders sharing overlapping pathological mechanisms. Several studies suggest that AD biomarkers may have diagnostic and predictive value in PD, but causal evidence remains insufficient. This study aimed to explore the association between AD-related biomarkers and PD. Bidirectional two-sample Mendelian randomization (MR) was performed using GWAS summary statistics of AD-related biomarkers and PD to assess causal relationships. Subsequently, single-nucleus RNA sequencing (snRNA-seq) of postmortem midbrain tissues was employed to examine the expression of AD biomarkers in PD patients and to explore underlying cellular signaling pathways. Forward MR revealed a significant causal association between PD and decreased CSF p-tau levels. PD progression showed significant causal associations with decreased CSF Aβ42 and increased CSF total tau. Reverse MR indicated that elevated CSF total tau may increase PD risk. SnRNA-seq analysis demonstrated that MAPT (encoding tau) was predominantly expressed in dopaminergic neurons, with differentially expressed genes enriched in PD- and neurodegeneration-related pathways. Our findings provide preliminary, hypothesis-generating evidence at the genetic level suggesting potential associations between CSF tau, Aβ42, and PD or its progression. Bidirectional MR analyses suggest that CSF total tau may be associated with increased PD risk, while exploratory snRNA-seq analysis indicates that MAPT is predominantly expressed in dopaminergic neurons with enrichment in PD-related pathways. Given the limited number of instrumental variables for several exposures, the small snRNA-seq cohort, and the absence of protein-level validation, these findings should be interpreted with caution. Large-scale prospective clinical studies with protein-level biomarker assessment, tau-PET imaging, and independent multi-cohort transcriptomic validation are warranted before CSF total tau can be considered a candidate biomarker for PD progression.