Cellular and Molecular Neurobiology最新文献

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.

Spinal cord injury (SCI) is one of the most common critical illnesses, which can cause neurological deficits and disabilities of motor, sensory and autonomic nervous system in mild cases, and lead to paralysis or even death following severe trauma. Although there are currently no effective and satisfactory clinical treatments, the efforts for repair SCI never stop. Besides the traditional strategies such as drugs, surgical interventions and rehabilitative care, the bionic therapies have attracted significant attention due to its considerable promise. The bionic therapies for SCI mainly included engineered biomaterials-based approaches aiming for reconstruction of internal neural circuit and brain machine interfaces (BMI)-based technologies to integrate extrinsic control and intrinsic circuit. This review provides an extensive overview of SCI research and bionic therapies, with focus on reconstruction and integration of neural circuit, which might provide promising insights on clinical treatment.

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Extracellular senile plaques composed of amyloid-β (Aβ) peptides, intracellular neurofibrillary tangles (NFTs) containing the hyperphosphorylated tau protein, excessive production of reactive oxygen species (ROS) and neuroinflammation are crucial contributing factors to the pathological mechanisms of AD. The nonreceptor tyrosine kinase c-Abl plays a complex dual role in AD through the regulation of signaling pathways such as oxidative stress, DNA repair, and apoptosis. c-Abl mitigates early neuronal damage by activating antioxidant enzymes and potentially promoting homologous recombination (HR) repair. However, its aberrant activation is associated with Aβ plaque formation, tau phosphorylation, neuronal cell death, and synaptic dysfunction. Its synergistic interaction with Aβ and tau exacerbates the neurodegenerative pathology. This article provides a systematic review of the molecular mechanisms of c-Abl in AD, including its dual role in oxidative stress, synergistic regulation of neuronal function with Aβ and the tau protein, involvement in the maintenance of genomic stability, and potential as a therapeutic target.

Gliomas are complex and among the most lethal central nervous system (CNS) disorders. While they are notoriously heterogeneous, evidences suggest critical involvement of intricate interactions between RNA-binding proteins (RBPs) and their diverse partners, in the pathogeneses of gliomas. In this study, we used RNA sequencing data from the Cancer Genome Atlas (TCGA) to identify differentially expressed genes (DEGs). After selection of differentially expressed RBPs from these DEGs, systematic investigation of their transcriptomic changes during glioma progression was undertaken. Extensive in silico assessments allowed the creation of their interactome and pathway, identifying potential biological effects of these differentially expressed RBPs. Construction of regulatory networks of these differentially expressed RBPs and their topological analysis discovered key RBPs such as PABPC1, EIF4A2, RPS3, EEF1A1, RPS6, ELAVL2, CPEB1, and CELF5, which are largely involved in alternative splicing and ribosomal biogenesis. Moreover, we also identified differentially expressed RBPs such as YBX1, ELAVL2, and IGF2BP1, which may be involved in the formation of stress granules in gliomas. We also identified highly mutated RBPs, such as RPSA, RPL5, CPEB4, and SMAD7, in gliomas. Further, RBPs like RPS8, RPL5, RPS3A, EEF1A1, and EIF4E1B were found to be strongly correlated with patients' overall survival. Taken together, our analyses identified several candidate RBPs which might serve as potential targets for oncological measures against gliomas.

The parasympathetic nervous system (PNS), a division of the autonomic nervous system, maintains physiological homeostasis within the body. The PNS seems to influence the processing of nociceptive information. A growing body of research indicates that the PNS actively contributes to various pain conditions associated with inflammation of tissues and/or neural damage. Therefore, the aim of this review is to integrate current findings regarding the peripheral parasympathetic pathways implicated in pain, encompassing direct cholinergic actions and indirect effects on the sensory nervous system. Enhanced insight into PNS-sensory interactions in pain could provide a basis for identifying new strategies for the prevention and management of pain conditions.

The interaction between lipid droplet (LD) metabolism and immune polarisation of microglia after stroke plays a key role in the regulation of neuroinflammation and tissue repair. This review analysed the molecular mechanism, spatiotemporal specificity, and the dual role of the LD metabolism-immune axis in microglia after stroke. Microglial LDs can dynamically store neutral lipids and regulate the metabolite-immune network, playing a protective role in the early stage of stroke by isolating pro-inflammatory precursors, inhibiting oxidative stress and iron death, and maintaining energy buffer. Spatiotemporal analysis revealed significant heterogeneity in the distribution and function of LDs across different stages of stroke and in distinct brain areas (infarct core, peri-infarct region, and non-infarct area), directly correlating with the pro-inflammatory/anti-inflammatory phenotypic transformation of microglia. The development of LD-related biomarkers (such as near-infrared imaging), the repurpose of peroxisome proliferator-activated receptor γ agonists (rosiglitazone) and HDAC inhibitors (volinostat), as well as the design of novel drugs (such as Triggering Receptor Expressed on Myeloid Cells 2 agonists and perilipin 2 small interfering RNA) are expected to improve stroke outcomes by transforming metabolic homeostasis and immune balance. Multi-omics technology and intelligent delivery system should be combined to overcome the limitations of the blood-brain barrier, promote the clinical transformation of the "metabolism-immunity" collaborative intervention strategy, and provide a new paradigm for precision treatment of stroke.

HIV-1-associated neurocognitive disorders (HAND) are highly prevalent in the era of combination of antiretroviral therapies. Recent studies suggest that damage of blood-brain barrier (BBB) may serve as an early biomarker of cognitive dysfunction in people living with HIV. This is due to the ability of HIV-1, along with infected monocytes and macrophages, to traverse the BBB via either paracellular or transcellular way. HIV-1 viral proteins have been shown to disrupt tight junctions within the BBB, thereby directly compromising its structural and functional integrity. This study determined the effects of the HIV-1 transactivator of transcription (Tat) protein on the morphological profiles and gene expression of mouse prefrontal cortex endothelial cells (ECs) and human brain microvascular endothelial cells (HBMVEC). Both mouse ECs and HBMVEC were exposed in vitro to 12.5 nM recombinant Tat_1-86 for 48 h. After treatment, cells were immunostained with CD31, DAPI or phalloidin, and harvested for RNA sequencing to access changes in gene expression. Staining results showed a reduction in CD31 expression accompanied by an increase in phalloidin staining intensity in both mouse ECs and HBMVECs after Tat exposure. Moreover, the phalloidin staining revealed disruption of actin cytoskeleton structure in both mouse ECs and HBMVECs after Tat exposure. RNA sequencing analysis of mouse ECs and HBMVECs exposed to Tat displayed strikingly comparable transcriptomic signatures, as confirmed by gene set enrichment analysis (GSEA). In particular, both mouse ECs and HBMVECs showed significant upregulation of hallmark inflammatory response pathways following Tat exposure. These findings provide mechanistic insight into HIV-1 Tat drives endothelial injury, leading to both morphological and transcriptional alterations.

Stroke remains a major global health challenge due to its high mortality and significant socioeconomic burden. Despite advances in clinical management, effective diagnostic tools and therapeutic strategies remain limited. This study aimed to identify and expand the repertoire of biomarkers of damage and repair that could serve as potential diagnostic and prognostic tools across post-stroke phases. Twenty-three male wild-type mice were assigned according to three longitudinal time points to control pre-stroke, 24-hour acute, and 35-day chronic post-stroke groups. Ischemic injury was induced via a 30-minute middle cerebral artery occlusion Koizumi method. Magnetic resonance imaging and neurological scoring were used to assess lesion size and functional deficit acutely, as well as structural and functional recovery during the chronic phase. Proteomic profiling of the ipsilateral and contralateral cortices was performed using data-independent acquisition (DIA)-based MS method. Statistical analysis revealed 74 differentially expressed proteins showing significant temporal changes in expression, which were classified into four temporal expression clusters: acutely and chronically upregulated, acutely upregulated and chronically downregulated, acutely downregulated and chronically upregulated, and acutely and chronically downregulated. Gene ontology analysis identified 47 affected biological processes, including synaptic signaling, immune response, cell-cell communication, cytoskeletal organization, and proliferation. Thirteen proteins previously not associated with stroke pathophysiology were identified, including 10 from the ipsilateral cortex (Dbi, Cpne3, Dnm2, Eef1a1, Taldo1, Pgls, Gnb5, Phf24, Ctsz, Capg) and 3 from the contralateral cortex (Agpat3, Cacng8, Endod). The identified biomarkers provide novel molecular insights into post-stroke energy metabolism, neuroinflammation, and cellular remodeling, highlighting potential targets for further intervention.

Alzheimer's disease (AD) still lacks a conclusive treatment, largely due to an incomplete understanding of the molecular mechanisms involved. To enhance our knowledge of AD pathogenesis and identify potential therapeutic targets, this study integrates differential gene expression analysis, pathway enrichment, hub gene discovery, protein-protein interaction (PPI) clustering, and transcription factor/protein kinase regulation into a single, cohesive pipeline. This comprehensive systems-level approach moves beyond single-gene analyses to offer a broader, mechanistically focused insight into AD biology. Using RNA-seq data from the CA1 region of the hippocampus-a subregion selectively affected in early AD-we identified 1,104 differentially expressed genes (DEGs). Among the enriched pathways, "7-alpha-hydroxycholesterol" was upregulated, while "vacuolar organization" was downregulated in AD samples. Furthermore, five novel hub genes (MRPS7, RPL5, GFM1, RAD51, and ASPM) were identified within the PPI network. The first three-MRPS7, RPL5, and GFM1-along with ACO2 and MT-ATP6, are potentially linked to hereditary forms of AD due to their roles in mitochondrial function. We also discovered four collaborative clusters within the network that notably associated with the "inflammatory response", "7-alpha-hydroxycholesterol", "Mitochondrial dysfunction" and "Oxidative phosphorylation" pathways, making them promising candidates for therapeutic and diagnostic investigation due their behavioral information members. Additionally, we identified ten transcription factors (GATA2, CHD1, THRA, IRF7, ZBTB48, POLE4, ZNF219, SLC2A4RG, NR1D1, and RXRA) and one protein kinase (PRKCZ) as potential regulatory elements in AD. This study broadens our understanding of Alzheimer's disease by identifying five candidate hub genes, two functional PPI clusters, two signaling pathways, and eleven regulatory proteins, thereby laying the groundwork for future therapeutic and diagnostic developments in molecular AD research.

Early-life exposure to light at night can disrupt the maturation of the circadian system and lead to long-lasting behavioural and molecular alterations. We exposed rat pups to constant light (LL; 16 lx) from birth (P0) to postnatal day 20, followed by a standard light-dark cycle (LD 12:12). At postnatal day 60, anxiety-like behaviour was assessed using the open field, elevated zero maze, and light/dark box. In parallel, we analysed circadian gene expression rhythms in the hippocampus, parietal cortex, frontal cortex, and olfactory bulbs, and examined A-to-I RNA editing and splicing in the hippocampus at P30. LL exposure increased body weight in males and tended to enhance anxiety-like behaviour, particularly in females. Locomotor activity during behavioural testing was reduced in both sexes, whereas circadian rhythms in constant darkness remained intact. At the molecular level, LL disrupted circadian gene expression in a brain region- and sex-specific manner. The hippocampus in males showed widespread loss of rhythmicity, while the parietal cortex was more affected in females. LL also reduced Adar2 expression rhythmicity and editing efficiency at functionally relevant sites in Gria2 and Htr2c, suggesting altered coupling between R/G editing and alternative splicing in Gria2. These findings demonstrate that low-intensity LL during a critical postnatal window can induce long-lasting, sex-specific alterations in behaviour and gene regulation. Our data provide the first mechanistic insight into how early environmental light exposure may shape long-term emotional and neurobiological outcomes.