Search Results (165)

Alzheimer’s disease (AD) is a neurodegenerative disease with a multifaceted pathogenesis, which remains elusive, seriously affecting the quality of life of elderly patients and placing a heavy burden on affected individuals, their families, and society. As third-party synapses in brain networks, astrocytes play an important role in maintaining the normal function of neural networks, which contribute to the abnormal function of networks in AD. In recent years, numerous studies have shown that clusterin, a protein expressed by astrocytes, can participate in the progression of AD. Clusterin plays a significant role in many pathological processes of AD, such as lipid metabolism, AD pathological features, the imbalance in neural circuit excitatory inhibition, and neuroinflammation. Therefore, delving deeper into the association between clusterin and AD will help us to understand the mechanisms of disease better and provide a theoretical basis for early diagnosis and the development of treatment strategies for AD. Full article

Background: Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), are genetically complex and often linked to structural genomic variations such as copy number variants (CNVs). Current diagnostic strategies face challenges in interpreting the clinical significance of such variants. Methods: We developed a customized, gene-oriented chromosomal microarray (CMA) targeting 6026 genes relevant to neurodevelopment, aiming to improve diagnostic yield and candidate gene prioritization. A total of 39 patients with unexplained developmental delay, intellectual disability, and/or ASD were analyzed using this custom platform. Systems biology approaches were employed for downstream interpretation, including protein–protein interaction networks, centrality measures, and tissue-specific functional module analysis. Results: Pathogenic or likely pathogenic CNVs were identified in 31% of cases (9/29). Network analyses revealed candidate genes with key topological properties, including central “hubs” (e.g., NPEPPS, PSMG1, DOCK8) and regulatory “bottlenecks” (e.g., SLC15A4, GLT1D1, TMEM132C). Tissue- and cell-type-specific network modeling demonstrated widespread gene involvement in both prenatal and postnatal developmental modules, with glial and astrocytic networks showing notable enrichment. Several novel CNV regions with high pathogenic potential were identified and linked to neurodevelopmental phenotypes in individual patient cases. Conclusions: Customized CMA offers enhanced detection of clinically relevant CNVs and provides a framework for prioritizing novel candidate genes based on biological network integration. This approach improves diagnostic accuracy in NDDs and identifies new targets for future functional and translational studies, highlighting the importance of glial involvement and immune-related pathways in neurodevelopmental pathology. Full article

Background: With an aging population, dementia prevalence is increasing in Korea. Vascular dementia (VaD), often caused by cerebrovascular disease (CVD), is more common in Korea compared to Western countries. Hwanhon decoction, a traditional medicine containing Ephedrae Herba, Armeniacae Semen, and Glycyrrhizae Radix et Rhizoma, is traditionally used for CVD-related loss of consciousness. This study aimed to assess the cognitive improvement and anti-inflammatory effects of Hwanhon decoction extract (HHex) in a mouse model of VaD caused by chronic cerebral hypoperfusion (CCH). Methods: Key pharmacologically active ingredients of Hwanhon decoction were identified using network pharmacology analysis. VaD was induced in C57Bl/6 male mice through bilateral common carotid artery stenosis (BCAS). Mice were divided into sham surgery, BCAS control, low-dose HHex (L-HHex), and high-dose HHex (H-HHex) groups (n = 5/group). After CCH induction, L-HHex or H-HHex was administered thrice weekly for six weeks. Cognitive function, inflammatory markers, and RNA sequencing data were analyzed. Results: HHex administration reduced cognitive impairment and mitigated CCH-induced astrocyte activation. Inflammatory responses mediated by reactive astrocytes were suppressed, and network pharmacology predicted central proteins influencing HHex’s activity. Conclusions: HHex alleviated cognitive dysfunction and reduced inflammation in a VaD mouse model, suggesting its potential as a therapeutic agent for vascular dementia associated with impaired cerebral blood flow. Full article

The neurological basis of consciousness remains unknown despite innumerable theories proposed for over a century. The major obstacle is that empirical studies demonstrate that all sensory information is subdivided and parcellated as it is processed within the brain. A central region where such diverse information combines to form conscious expression has not been identified. A novel hypothesis was introduced over two decades ago that proposed astrocytes, with their ability to interconnect to form a global syncytium within the neocortex, are the locus of consciousness based on their ability to integrate synaptic signals. However, it was criticized because intercellular calcium waves, which are initiated by synaptic activity, are too slow to contribute to consciousness but ideal for memory formation. Although astrocytes are known to exhibit rapid electrical responses in active sensory pathways (e.g., vision), it was technically impossible to determine electrical activity within the astroglia syncytium because of the challenge of separating syncytial electrical responses from simultaneous neuronal electrical activity. Therefore, research on astroglia syncytial electrical activity lagged for over sixty years, until recently, when an ingenuous technique was developed to eliminate neuronal electrical interference. These technical advances have demonstrated that the astroglia syncytium, although massive and occupying the entire neocortex, is isoelectric with minimal impedance. Most importantly, the speed of electrical conductance within the syncytium is as rapid as that of neural networks. Therefore, the astroglia syncytium is theoretically capable of transmitting integrated local synaptic signaling globally throughout the entire neocortex to bind all functional areas of the brain in a timeframe required for consciousness. Full article

Abnormal deposition of β-amyloid (Aβ) is a core pathological feature of Alzheimer’s disease (AD). Syndecan-3 (SDC3), a type I transmembrane heparan sulfate proteoglycan (HSPG), is abnormally overexpressed in the brains of AD patients and model animals, specifically accumulating in the peri-plaque region of amyloid plaques. However, its regulatory mechanism in the process of Aβ deposition remains unclear. This study aims to clearly define the role of SDC3 in Aβ aggregation and neuroinflammation, two critical processes in AD pathogenesis. Specifically, we investigate how SDC3 modulates Aβ aggregation and its interaction with neuroinflammatory pathways, which may contribute to the progression of AD. By elucidating the mechanisms underlying SDC3’s involvement in these processes, we seek to provide new insights into potential therapeutic targets for AD. In this study, a 5×FAD mouse model with downregulated SDC3 expression was constructed. Behavioral assessments and synaptic function tests were performed to explore the effects of SDC3 on cognition in 5×FAD mice. Immunofluorescence co-localization technology was utilized to analyze the pathological co-deposition of SDC3 and Aβ in the hippocampus, cortex, and meningeal blood vessels. Quantitative assessments of pro-inflammatory cytokines such as Tnf-α and Cxcl10 in the brain were performed through histopathological analysis combined with qPCR. Western blotting was used to examine the phosphorylation status of STAT1/STAT3 and the expression changes of IBA1/GFAP to systematically analyze the molecular mechanisms through which SDC3 regulates AD pathology. This study revealed that SDC3 expression was significantly upregulated in the brain regions of the 5×FAD model mice and co-localized pathologically with Aβ. Cell lineage tracing analysis showed that the elevated SDC3 expression primarily originated from glial cells. Behavioral and pathological results demonstrated that downregulation of SDC3 significantly improved cognitive dysfunction in the model mice and effectively reduced the Aβ burden in the brain. Molecular mechanism studies showed that downregulation of SDC3 reduced the phosphorylation of STAT1 and STAT3, thereby inhibiting the activation of the JAK-STAT and cGAS-STING signaling pathways, reducing the activation of microglia/astrocytes and suppressing the expression of pro-inflammatory cytokines such as Tnf-α and Cxcl10. This study reveals that SDC3 co-localizes with Aβ pathology and synergistically exacerbates neuroinflammation. Knockdown of SDC3 can simultaneously reduce both Aβ deposition and the release of inflammatory factors from glial cells. Mechanistic research indicates that SDC3 drives a “glial activation–cytokine release” vicious cycle through the JAK-STAT and cGAS-STING signaling pathways. These findings suggest that SDC3 may serve as a key hub coordinating amyloid pathology and neuroinflammation in AD, providing new insights for the development of combination therapies targeting the HSPG network. Full article

Alzheimer’s disease (AD) is a neurodegenerative condition characterized by considerable cognitive decline and functional impairment, primarily due to the progressive alteration of neurons, microglia, and astrocytes. Pathological manifestations of AD include the loss of synaptic plasticity, reduction in synaptic strength by amyloid-beta, aggregation, and neurotoxicity from tau protein post-translational modifications, all contributing to the disruption of neural networks. Despite its current pharmacological treatment for AD, different approaches to treat such disease are being developed, from a microbiome perspective. The microbiome encompasses a diverse microorganism, including beneficial bacteria that create a positive impact to diminish AD pathogenesis. Growing evidence suggests that probiotic, prebiotic, synbiotic, and postbiotics can positively modulate the gut–brain axis, reducing systemic inflammation, restoring neurotransmitter balance, and improving gut health, thereby possibly mitigating AD pathogenesis. Moreover, there is paraprobiotics as the most recently developed biotherapeutic with beneficial effects. This review explores the correlation between AD and gut–brain axis as a novel biotherapeutic target. The underlying mechanism of the microbiota–gut–brain axis in AD is examined. Novel insights into the current applications as potential treatment and its limitations are highlighted. Full article

Primary cultures of neural cells are important key tools for basic and translational neuroscience research. These primary cell cultures are classically generated from the rodent brain hippocampus or cortex and optimized for enrichment in neurons at the expense of glial cells. Importantly, considerable differences exist in neuronal cell populations and in glial cell contribution between different brain regions. Because many basic and translational research projects aim to identify mechanisms underlying brainstem neuronal networks that affect major vital functions, primary cultures representative of cell populations present in the hindbrain are required. However, the preparation of primary cultures of brainstem/hindbrain neurons is scarcely described in the literature, limiting the possibilities for studying the development and physiology of these brain regions in vitro. The present report describes a reliable protocol to dissociate and culture in vitro embryonic mouse fetal hindbrain neurons in a defined culture medium, while control of astrocytes’ expansion was attained by using a chemically defined, serum-free supplement, namely CultureOne™. The neuronal cells maintained according to this protocol differentiate and, by 10 days in vitro, they develop extensive axonal and dendritic branching. Using immunofluorescence, we further characterized the different cell populations and neuronal subtypes. Patch–clamp recordings demonstrate the excitable nature of these neurons, while colocalization of pre- and postsynaptic neuronal markers showed that neurons form mature synapses, suggesting the establishment of functional networks in vitro. The cultures produced by this method show excellent reproducibility and can be used for molecular, biochemical, and physiological analyses, as illustrated here for tamoxifen-induced Cre recombination in genetically-modified neural cells. Full article

While the greatest risk factor for Alzheimer’s disease (AD) is aging, women are disproportionately affected by the disease. Interestingly, the hippocampus and cerebellum exhibit gender-specific cytoarchitecture differences, which are associated with AD, despite the absence of a role in animal reproductive behavior or hormonal signaling. This study investigates the potential association of sex differences associated with AD by interrogating cerebellar and hippocampal volume in preclinical (MCI) as well as clinical phases of AD compared to cognitively normal patients (CN) and in an animal model of AD, the streptozotocin (STZ)-induced sporadic AD model. In order to investigate putative changes in cerebellum and hippocampus in a rat model of AD, we used a STZ-induced sporadic AD model at three different time points (2, 4, and 8 weeks) after surgery in male and female rats. Previous studies have reported hippocampal-dependent changes as well as sex-dependent behavioral and signaling effects in the STZ animal model of sporadic AD while our current study showed involvement of cerebellum-mediated changes. To interrogate the role of cerebellar volume in AD progression within the human context, we analyzed data available through the Alzheimer’s Disease Neuroimaging Initiative (ADNI). In a cross-sectional analysis, we observed that levels of peripheral Glial Acidic Fibrillary Protein (GFAP) (astrocytic protein) were associated negatively with cerebellar and hippocampal volumes (β = −0.002, p-value = 0.04; β = −6.721, p-value < 0.0001) and were associated with sex specific differences in males. Our analysis identified that the effect on hippocampal volume was earlier in disease stage, reinforcing the relevance of longitudinal alterations of cerebellum and hippocampus volume over time. The STZ animal model of sporadic AD, corroborated the progressive changes in hippocampal volume and more minor and temporally delayed involvement of the cerebellum volume changes which were dependent on sex. This suggests that cerebellar involvement may be secondary to hippocampal neurodegeneration, and both regional differences were dependent on sex. Due to the association with GFAP, our findings may be due to network astrocyte connection spread regardless of primary pathology. Overall, our study uncovers a novel role for cerebellum in AD in a model and in the human context. Full article

Background/Objectives: Epilepsy is a common neurological disorder that not only severely impacts patients’ health but also imposes a significant burden on families and society. However, its pathogenesis remains unclear. Astrocytes play a crucial role in epileptic seizures and may serve as potential therapeutic targets. Establishing a network model of epileptic seizures based on the astrocyte–neuron cell coupling and the clinical electroencephalographic (EEG) characteristics of epilepsy can facilitate further research on refractory epilepsy and the development of treatment strategies. Methods: This study constructs a neuronal network dynamic model of epileptic seizures based on the Watts–Strogatz small-world network, with a particular emphasis on the biological mechanisms of astrocyte–neuron coupling. The phase-locking value (PLV) is used to quantify the degree of network synchronization and to identify the key nodes or connections influencing synchronous seizures, such that two epilepsy treatment strategies are proposed: seizure suppression through stimulation and surgical resection simulation therapy. The therapeutic effects are evaluated based on the PLV-quantified network synchronization. Results: The results indicate that the desynchronization effect of random noise and sinusoidal wave stimulation is limited, while square wave stimulation is the most effective. Among the four surgical resection strategies, the effectiveness is the highest when resecting nodes exhibiting epileptic discharges. These findings contribute to the development of rational seizure suppression strategies and provide insights into precise epileptic focus localization and personalized treatment approaches. Full article

Penetrating traumatic injuries of the brain have a poor clinical prognosis necessitating development of new therapies to improve neurological outcomes. Laboratory research is hampered by reliance on highly invasive experimental approaches in living animals to simulate penetrating injuries e.g., by cutting/crushing the brain tissue, with a range of associated ethical, technical and logistical challenges. Accordingly, there is a critical need to develop neuromimetic in vitro alternative neural models to reduce harm to animals. However, most in vitro, reductionist simulations of brain injury are too simplistic to simulate the complex environment of the injured nervous system. We recently reported a complex, two-dimensional in vitro mouse model of neurotrauma containing five major brain cell types to replicate neural architecture, grown on a “hard” glass substrate in a brain cell sheet. We now demonstrate the translation of this approach into a three-dimensional tissue injury model, by propagating the entire cellular network in a “soft” compliant collagen hydrogel, similar to native brain tissue stiffness (an important determinant of cell fate). A multicellular network of neural cells was observed to form in the polymer matrix containing all major brain cell populations, including the immune cells (microglia). We demonstrate that it is feasible to create a reproducible, focal traumatic injury in the synthesised neural tissue construct. Importantly, key pathological features of neurological injury, such as astrocyte scarring, immune cell (microglial) activation, impeded axonal outgrowth and stem/progenitor cell migration, can be successfully induced. We also prove that it is feasible to implant a biomaterial into the lesion gap to study neural cell responses for screening applications. The findings support the concept that the model can be used in a versatile manner for advanced neural modelling. Full article

Intermediate filament protein vimentin (Vim) is a well-established marker for reactive astrocytes and has been closely associated with Alzheimer’s disease (AD). RNA sequencing data reveal elevated expression of Vim in AD brains, with its aggregation frequently observed around amyloid-β (Aβ) plaques. However, the precise mechanisms by which Vim influences the aggregation or propagation of Aβ plaques remain unclear. In this study, we detected the upregulation of astrocytic Vim in AD brain tissue, with its co-localization around Aβ plaques. Asparagine endopeptidase (AEP), another molecule implicated in AD, was found to cleave Vim both in vitro and in vivo, including within human brain tissue. Mass spectrometry analysis confirmed that the AEP cleavage site on Vim is located at N283. We further investigated the in vivo cellular localization of Vim and observed that fragmented Vim, particularly the C-terminal fragment Vim 284–466, promotes apoptosis and disrupts the network structure that is essential for interaction with glial fibrillary acidic protein (GFAP). This disruption impairs astrocytic phagocytosis of exogenous Aβ, which is attributed to the reduced release of apolipoprotein E (ApoE) by astrocytes. The decrease in ApoE levels, in turn, diminishes the transport and clearance of Aβ. Conversely, mutation of the Vim N283 site (N283A) prevents AEP-mediated cleavage of Vim, preserves the GFAP network structure, restores ApoE levels, and reverses the effects on Aβ aggregation. Collectively, our findings elucidate the role of Vim fragmentation in Aβ plaque deposition and propose a potentially novel therapeutic strategy for Alzheimer’s disease. Full article

Background/Objectives: Learning disabilities (LDs) are complex neurodevelopmental conditions influenced by genetic, epigenetic, and environmental factors. Recent research suggests that maternal autoimmune conditions, perinatal stress, and vitamin D deficiency may contribute to neuroinflammation, which, in turn, can disrupt brain development. Chronic neuroinflammation, driven by activated microglia and astrocytes, has been associated with synaptic dysfunction and cognitive impairment, potentially impacting learning and memory processes. This study aims to explore the relationship between neuroinflammation and LDs, emphasizing the role of electroencephalography (EEG) biomarkers in early diagnosis and intervention. Methods: A systematic analysis was conducted to examine the prevalence, core symptoms, and typical age of diagnosis of LDs. EEG biomarkers, particularly theta, gamma, and alpha power, were assessed as indicators of neuroinflammatory states. Additionally, artificial neural networks (ANNs) were employed to classify EEG patterns associated with LDs, evaluating their diagnostic accuracy. Results: Findings indicate that EEG biomarkers can serve as potential indicators of neuroinflammatory patterns in children with LDs. ANNs demonstrated high classification accuracy in distinguishing EEG signatures related to LDs, highlighting their potential as a diagnostic tool. Conclusions: EEG-based biomarkers, combined with machine learning approaches, offer a non-invasive and precise method for detecting neuroinflammatory patterns associated with LDs. This integrative approach advances precision medicine by enabling early diagnosis and targeted interventions for neurodevelopmental disorders. Further research is required to validate these findings and establish standardized diagnostic protocols. Full article

Neuromimetic in vitro models, simulating in vivo architecture/organization, are urgently needed to reduce experimental reliance on live animals. Our group recently reported a novel brain tissue derivation protocol, simultaneously deriving all major cortical cell types (including immune cells) in a facile protocol, generating a network of neurons in a single growth medium, which was interfaced with nanomaterials. This represents a significant advance, as tissue engineers overwhelmingly use diverse methods to derive and combine individual brain cells for materials-interfacing. However, this multicellular model lacked cellular directionality/structural organization (unlike the highly organized cortical circuits in vivo). Synthetic nanofiber constructs are of high value in tissue engineering, providing directional cues for cells. Most neuro-nanofiber studies employ simple monocultures of astrocytes/neurons and commonly use peripheral neurons rather than central nervous system populations. Here, we have interfaced our complex brain model (neurons/astrocytes derived simultaneously) with randomly oriented or aligned polycaprolactone (PCL) fiber meshes. Both cell types showed targeted extension along aligned fibers versus coverslips or random fibers. A new analysis method developed in-house demonstrated that peak orientations for astrocytes and neurons correlated with aligned nanofibers. Our data support the concept that nanofiber scaffolds can achieve organized growth of mixed cortical neural cell populations, mimicking neural architecture. Full article

Glial fibrillary acidic protein (GFAP) is classified as a type III intermediate filament protein predominantly expressed in mature astrocytes. It has the ability to self-assemble into 10 nm filaments in vitro, making it particularly valuable for elucidating the sequences essential for filament assembly. In this study, we created a series of deletion mutants targeting sequences in the N-terminal, C-terminal, and central rod domains to explore the sequences critical for the assembly of GFAP into 10 nm filaments. The impact of these deletions on filament formation was evaluated through in vitro assembly studies and transduction assays conducted with primary astrocytes. Our data revealed that deletions at the carboxy end resulted in abnormalities in either filament diameter calibration or lateral association, whereas deletions at the amino-terminal end significantly disrupted the filament assembly process, particularly restricting filament elongation. Furthermore, we discovered that the filament-forming sequences within the rod domain varied in their contributions to filament assembly and network formation. These findings enhance our understanding of the GFAP assembly process in vitro and provide a detailed mapping of the essential regions required for GFAP assembly. These insights hold significant implications for Alexander disease arising from deletion mutations in GFAP. Full article

Proteins involved in synaptic transmission in normal hearing, acoustic stimulation, and tinnitus were identified using protein–protein interaction (PPI) networks. The gene list for tinnitus was compiled from the GeneCards database using the keywords “synaptic transmission” AND “inferior colliculus” AND “tinnitus” (Tin). For comparison, two gene lists were built using the keywords “auditory perception” (AP) and “acoustic stimulation” (AS). The STRING and the Cytoscape data analyzer were used to identify the top two high-degree proteins (HDPs) and the corresponding high-score interaction proteins (HSIP). The top1 key proteins of the AP and AS processes are BDNF and the receptor NTRK2; the top2 key proteins in the AP process are PVALB, together with GAD1, CALB1, and CALB2, which are important for the balance of excitation and inhibition. In the AS process, the top2 key proteins are FOS, CREB1, EGR1, and MAPK1, reflecting an activated state. The top1 key proteins of the Tin process are BDNF, NTRK3, and NTF3; these proteins are associated with the proliferation and differentiation of neurons and indicate the remodeling of synaptic transmission in IC. The top2 key proteins are GFAP and S100B, indicating a role for astrocytes in the modulation of synaptic transmission. Full article