Frontiers in Molecular Neuroscience最新文献

Gliomas are the most common type of malignant primary central nervous system (CNS) tumors, resulting in significant morbidity and mortality in children and adolescent and young adult (AYA) patients. The discovery of mutations in isocitrate dehydrogenase (IDH) genes has dramatically changed the classification and understanding of gliomas. IDH mutant gliomas have distinct clinical, pathological, and molecular features including a favorable prognosis and response to therapy compared to their wildtype counterparts. Although more common in adults, 5-15% of pediatric gliomas have IDH mutations. In this review, we provide a comprehensive summary of the current knowledge on IDH mutant high-grade gliomas (HGG), including their biology, clinical features, diagnosis, treatment, and prognosis. We also discuss future directions in research and clinical management with particular attention to the AYA cohort.

Introduction: Endothelial-to-mesenchymal transition (EndoMT), cell death, and fibrosis are increasingly recognized as contributing factors to Alzheimer's disease (AD) pathology, but the underlying transcriptomic mechanisms remain poorly defined. This study aims to elucidate transcriptomic changes associated with EndoMT, diverse cell death pathways, and fibrosis in AD using the 3xTg-AD mouse model.

Methods: Using RNA-seq data and knowledge-based transcriptomic analysis on brain tissues from the 3xTg-AD mouse model of AD. This included pathway-level analysis of gene expression changes across multiple brain cell types. Mechanistic insights were further validated using single-cell RNA sequencing (scRNA-Seq) dataset from human AD brain.

Results: Our analysis showed that in the 3xTg-AD model: (i) multiple brain cell type genes are altered, promoting EndoMT through upregulation of RGCC and VCAN; (ii) genes related to various types of cell death, including apoptosis, ferroptosis, necrosis, anoikis, mitochondrial outer membrane permeability programmed cell death, mitochondrial permeability transition-driven necrosis, NETotic, and mitotic cell death, are upregulated in the several brain cell types; (iii) fibrosis-related genes are upregulated across multiple brain cell types. Further mechanistic analysis revealed: (1) mitochondrial stress through upregulation of mitochondrial genes in the brain cells; (2) upregulation of cellular, oxidative, and endoplasmic reticulum (ER) stress genes; (3) nuclear stress via upregulation of nuclear genes, transcription factors (TFs), and differentiation TFs FOSB and MEOX1; (4) metabolic reprogramming/stress through the upregulation of genes related to lipid and lipoprotein metabolism, fatty acid oxidation (FAO), glucose metabolism, and oxidative phosphorylation (OXPHOS); (5) catabolic stress via upregulation of catabolic genes. Single-cell RNA-Seq data indicated that many of these were also increased in AD patients' brain cells. These changes were reversed by knockdown of the ER stress kinase PERK (EIF2AK3) and deficiencies in FOSB and MEOX1.

Discussion: This study uncovers previously unrecognized molecular signatures of organelle stress and bioenergetic reprogramming that drive EndoMT, cell death, and fibrosis in AD. The reversal of these changes via PERK, FOSB, and MEOX1 inhibition highlights potential therapeutic targets for mitigating neurodegenerative processes in AD.

[This corrects the article DOI: 10.3389/fnmol.2025.1625943.].

Introduction: The potassium chloride co-transporter 2 (KCC2) is the principal Cl^- extrusion mechanism employed by mature neurons in the central nervous system (CNS) and plays a critical role in determining the efficacy of fast synaptic inhibition mediated by type A γ-aminobutyric acid receptors (GABA_ARs) to protect against epileptogenesis. It has previously been demonstrated that epileptic seizures down-regulate KCC2 and induce neuronal apoptosis through the extrinsic apoptotic pathway. However, the mechanism by which neuronal death is induced by KCC2 loss remains unknown. We have previously demonstrated that C1q copurifies with KCC2 in comparable amounts. C1q is responsible for synaptic elimination in the brain during development, aging and neurodegeneration.

Methods: Here, we studied apoptotic induction in models of KCC2 loss of function and demonstrated the importance of C1q in this process using a constitutive C1qKO mouse model. We characterized the activation of different apoptotic pathways by measuring caspase 8 and caspase 9 cleavage as markers of extrinsic and intrinsic apoptosis, respectively.

Results: This study demonstrates in vitro, ex vivo and following seizures in vivo, that reduced KCC2 function coincides with neuronal death by activating the extrinsic apoptotic pathway, which is contingent upon complement C1q. Moreover, kainic acid (KA)- and glutamate-induced excitotoxicity also selectively activates the extrinsic apoptotic pathway which is contingent upon C1q.

Discussion: These results strongly support the hypothesis that the KCC2/C1q protein complex plays a critical role in the apoptotic process that occurs following loss of KCC2 function.

Background: The occurrence of aneurysms is closely related to the growth and inflammatory response of vascular smooth muscle cells (VSMCs). The regulatory mechanism of ACTN2 in intracranial aneurysms (IA) has not yet been fully elucidated. This study aims to reveal the role of the PRDM9-ACTN2-PDLIM1 axis in the progression of aneurysms and its impact on VSMCs.

Methods: By integrating GEO datasets (GSE54083, GSE75436) and protein-protein interaction network analysis, ACTN2 was identified as a key gene. Techniques such as shRNA/overexpression, tissue staining, immunofluorescence, ELISA, and Western blot were used to analyze the effects of ACTN2 on VSMC proliferation, apoptosis, inflammation, and the Hippo pathway. The transcriptional regulation of ACTN2 by PRDM9 was validated through ChIP-qPCR, and the role of the PRDM9-H3K4me3-ACTN2 axis was explored using CRISPR-Cas9 experiments. PDLIM1 was screened as an interaction partner of ACTN2, and its role was verified through functional rescue experiments.

Results: α-actinin-2 (ACTN2) was significantly downregulated in IA tissues. Its knockdown exacerbated vascular wall damage, VSMC apoptosis, and the release of inflammatory factors by inhibiting the Hippo pathway. PRDM9 promoted ACTN2 transcription through H3K4me3 modification, and its low expression led to ACTN2 suppression, driving VSMC proliferation inhibition and promoting apoptosis and inflammation. PDLIM1 interacted with ACTN2, and its overexpression reversed the effects of ACTN2 knockdown, which depended on the Hippo-YAP signaling pathway.

Conclusion: This study reveals that PRDM9 regulates ACTN2 expression through epigenetic modifications and interacts with PDLIM1 to mediate VSMC function and aneurysm progression. The study provides a theoretical basis for clinical intervention.

Purpose: S-palmitic acid-9-hydroxy stearic acid (SP), a newly characterized endogenous lipid with multifaceted biological activities, is poised to shed light on its potential in diabetes-related cognitive disorder (DRCD). This study aims to uncover the effects of SP on DRCD and the underlying mechanisms.

Methods: C57BL/6 mice were fed with high-fat diet for 5 months to induce type 2 diabetes mellitus (T2DM). Subsequently, they received bilateral hippocampal injections of adeno-associated virus (AAV) carrying carbonic anhydrase III (CAIII) shRNA or control shRNA. Following one-month treatment with SP or vehicle, cognitive function was assessed using the Morris water maze and Y-maze tests. Oxidative stress and apoptosis were measured by Enzyme-linked Immunosorbent Assay (ELISA), and hippocampal neuronal morphology was examined through HE, Nissl, or NeuN staining. RNA sequencing (RNA seq), cell viability, tetramethylrhodamine ethyl ester (TMRE) staining, and mitoSOX assays were also performed in cultured PC12 cells.

Results: Our findings demonstrated that CAIII played a pivotal role in enhancing cognitive function in T2DM mice by improving spatial memory. SP ameliorated hippocampal injury by CAIII-mediated AMPK/Sirt1/PGC1α pathway, Bcl-2/Bax ratio elevation, and cleaved-Caspase 3 reduction. CAIII participated in various biological processes in the effects of SP on PC12 cells, including cell viability, lactate dehydrogenase (LDH) release, antioxidant enzymes, the maintenance of mitochondrial membrane potential, and the reduction of mitochondrial reactive oxygen species (ROS).

Conclusion: Our study revealed that CAIII was integral to the effects of SP on DRCD, suggesting its potential as a therapeutic target for DRCD.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the intracellular deposition of Tau protein and extracellular deposition of amyloid-β peptide (Aβ). AD is also characterized by neuroinflammation and synapse loss, among others. The S100 family is a group of calcium-binding proteins with intra- and extracellular functions, that are important modulators of inflammatory responses. S100B, which is upregulated in AD patients and the most abundant member of this family, was shown to inhibit in vitro the aggregation and toxicity of Aβ42, acting as a neuroprotective holdase-type chaperone. Although S100B is primarily produced by astrocytes, it is also expressed by various cells, including neurons. In this work, we investigated if S100B neuronal expression is triggered as a response to Aβ toxic species, to provide protection during disease progression. We used the AD mouse model AβPPswe/PS1A246E to show that neuronal S100B levels are significantly higher in 10-month-old animals, and cellular assays to demonstrate that Aβ oligomers significantly increase S100B expression in SH-SY5Y cells, but not monomeric or fibrillar Aβ. Using primary cultures of rat hippocampal neurons, we showed that S100B partially reverts Aβ-induced cofilin-actin rods (synapse disruptors), and rescues the decrease in active synapses and post-synaptic marker (PSD-95), imposed by Aβ peptide. Altogether, these findings establish the neuroprotective activity of S100B in response to proteotoxic stress in cells, highlighting its chaperone function as a crucial factor in understanding proteostasis regulation in the diseased brain and identifying potential therapeutic targets.

Postoperative cognitive dysfunction (POCD) remains a significant challenge in perioperative medicine, especially among older adults. Despite its prevalence, existing models centered on transient neuroinflammation fail to explain why cognitive deficits often persist long after systemic immune responses resolve. This review proposes a new framework: POCD is driven not by ongoing inflammation, but by a stable shift in microglial identity. We describe a closed-loop "inflammatory memory circuit" in which mitochondrial dysfunction, chromatin remodeling, and persistent polarization co-evolve to lock microglia into a hypersensitive, neurotoxic state. Recent studies suggest that surgical trauma triggers mitochondrial damage and mtDNA release, initiating innate immune activation via the cGAS-STING and NLRP3 pathways. These events engage epigenetic machinery-including HDAC3, DNMT3a, and long non-coding RNAs like MEG3-which reinforce transcriptional programs that lower activation thresholds and amplify cytokine output. Sustained M1-like polarization further propagates this loop, driving neuronal injury even in the absence of continued systemic cues. We outline experimental strategies to validate this model, including time-resolved single-cell transcriptomics and chromatin accessibility profiling. Therapeutically, we highlight HDAC inhibitors, SIRT1 agonists, and lncRNA-targeted interventions as potential strategies to disrupt the circuit before state-locking occurs. By reframing POCD as a glial fate transition rather than a transient immune reaction, this model offers mechanistic clarity and opens a path toward time-sensitive, precision interventions.