Search Results (387)

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

Globins are a class of globular proteins that function in the transportation or storage of oxygen. They are critical for cellular metabolism. Notable examples include hemoglobin, which is found in red blood cells, and myoglobin, which is present in muscle cells. Approximately two decades ago, a third globin, designated as neuroglobin, was identified, expressed predominantly in neuronal cells. This was followed two years later by the fourth, cytoglobin, found in cells of the fibroblast lineage, as well as in neuronal cell populations of the central and nervous systems. Both neuroglobin and cytoglobin have been found in the sensory and endocrine systems, albeit inconsistently, and it is thought that they are engaged in functions such as oxygen transport and storage, scavenging of free radicals, NO metabolism, peroxidase activity, and signaling functions. Neuroglobin is also expressed in astrocytes under challenging conditions. Common neuroscience methods were utilized to study the distribution and regulation of globin tissues and of single brain cells. Despite considerable overlap in the findings of various studies, some results deviate significantly from other studies. The potential causes of these discrepancies may include variations in detection methods, animal age and sex, time of day and year, and differing cell culture conditions. This review will explore factors that may influence functional aspects of globins and their detection in the mammalian brain. Full article

Background/Objectives: Depression is frequently comorbid with obesity. We previously showed that astrocyte-mediated hyperactive ventral hippocampal glutamatergic afferents to the nucleus accumbens determined the exhibition of depression-like behaviors in obese murine models. However, it remains unclear if the metabolic disorder-induced depressive phenotypes and astrocytic maladaptation in the ventral hippocampus (vHPC) could be reversed following the amelioration of key metabolic impairments such as insulin resistance and dyslipidemia. Method: Male mice were fed a high-fat diet (HFD) for 12 weeks, followed by either continued HFD feeding (HFD/HFD group) or a switch to a standard diet for 4 weeks (HFD/SD group). Results: Results showed that HFD/HFD mice displayed not only glucose/lipid metabolic dysfunction, but also depression-like behaviors. In contrast, HFD/SD mice showed improvements in metabolic disorders and depressive phenotypes. Mechanistically, dietary fat reduction restored astrocyte morphology and glutamate transporter expression (GLT-1, GLAST) in the vHPC and suppressed neuroinflammatory signaling, as evidenced by reduced levels of phospho-IKK, TNF-α, IL-1β, and IL-6 in the vHPC. Conclusions: These findings suggest that dietary fat reduction reverses obesity-induced depressive phenotypes, astrocytic deficits, at least in part via suppression of neuroinflammation through the NF-κB signaling pathway. Full article

Tissue hypoxia is commonly observed in head cancers and contributes to both molecular and functional changes in tumour cells. It is known to stimulate erythropoiesis, angiogenesis, and metabolic alterations within tumour cells. Glioblastoma, a type of brain tumour, is characterized by rapid proliferation and aggressive growth. Recent studies have indicated that natural products may hold potential as components of cancer therapy. Among these, Polish propolis and its active compound, quercetin, have demonstrated promising anti-cancer properties. The aim of this study was to evaluate the concentrations of selected cytokines—specifically IL-6, IL-9, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF-BB), interferon gamma-induced protein 10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1)—produced by astrocytes of the CCF-STTG1 cell line. The cytotoxic effects of ethanolic extract of propolis (EEP) and quercetin were assessed using the MTT assay. Astrocytes were stimulated with lipopolysaccharide (LPS, 200 ng/mL) and/or IFN-α (100 U/mL), followed by treatment with EEP or quercetin (25–50 µg/mL) under hypoxic conditions for two hours. Cytokine concentrations were measured using the xMAP Luminex Multiplex Immunoassay and the Multiplex Bead-Based Cytokine Kit. Our study demonstrated that Polish propolis and its component quercetin modulate the tumour microenvironment in vitro, primarily by altering the levels of specific cytokines. The HCA analysis revealed that IL-6 and MCP-1 formed a distinct cluster at the highest linkage distance (approximately 100% of Dmax), suggesting that their expression patterns are significantly different from those of the other cytokines and that they are more similar to each other than to the rest. PCA analysis showed that EEP-PL (50 μg/mL) with IFN-α and EEP-PL (50 μg/mL) with LPS exert similar activities on cytokine secretion by astrocytes. Similar effects were demonstrated for EEP-PL 50 μg/mL + LPS + IFN-α, EEP-PL 25 μg/mL + IFN-α and EEP-PL 25 μg/mL + LPS + IFN-α. Our findings suggest that Polish propolis and quercetin may serve as promising natural agents to support the treatment of stage IV malignant astrocytoma. Nonetheless, further research is needed to confirm these results. Full article

Background: Astrocytes are not only structural cells but also play a pivotal role in neurogenesis and neuroprotection by secreting a variety of neurotrophic factors that support neuronal survival, growth, and repair. This study investigates the time-dependent responses of primary rat cortical astrocytes to oxygen–glucose deprivation (OGD) and evaluates the neuroprotective potential of astrocyte-conditioned medium (ACM). Methods: Primary rat cortical astrocytes and neurons were obtained from postnatal Sprague Dawley rat pups (P1–3) and embryos (E17–18), respectively. Astrocytes exposed to 6, 24, and 48 h of OGD (0.3% O₂) were assessed for viability, metabolic function, hypoxia-inducible factor 1 and its downstream genes expression. Results: While 6 h OGD upregulated protective genes such as Vegf, Glut1, and Pfkfb3 without cell loss, prolonged OGD, e.g., 24 or 48 h, led to significant astrocyte death and stress responses, including elevated LDH release, reduced mitochondrial activity, and increased expression of pro-apoptotic marker Bnip3. ACM from 6 h OGD-treated astrocytes significantly enhanced neuronal survival following 6 h OGD and 24 h reperfusion, preserving dendritic architecture, improving mitochondrial function, and reducing cell death. This protective effect was not observed with ACM from 24 h OGD astrocytes. Furthermore, 6 h OGD-ACM induced autophagy in neurons, as indicated by elevated LC3b-II and decreased p62 levels, suggesting autophagy as a key mechanism in ACM-mediated neuroprotection. Conclusions: These findings demonstrate that astrocytes exhibit adaptive, time-sensitive responses to ischemic stress and secrete soluble factors that can confer neuroprotection. This study highlights the therapeutic potential of targeting astrocyte-mediated signalling pathways to enhance neuronal survival following ischemic stroke. Full article

Backgrounds/Objective: The impact of metabolic disturbances induced by an unbalanced diet on cognitive decline in mid-life is now widely observed, although the mechanisms are not well identified. Here we report that glutamatergic vasoactive pathways are a key feature of high-fat-diet (HFD)-induced neurogliovascular uncoupling in mice. Methods: C57Bl6/J mice are fed either with normal diet (ND) or high-fat diet (HFD) during 6 or 12 months and characterized for metabolic status. Cerebral vascular tree from pial to intraparenchymal arteries, is investigated with Halpern’s arteriography and with differential interference contrast infrared imaging of brain slices. Results: A 70% alteration in the myogenic tone of the basilar artery is observed as early as 6 months (M6) after the HFD. Infrared imaging revealed a 77% reduction in the glutamate-induced vasodilation of intraparenchymal arterioles appearing after 12 months (M12) of the HFD. The respective contributions of enzymes involved in glutamatergic pathways were altered as a function of HFD and time. The decrease in astrocytic COX I observed at M6 was followed by a loss of neuronal COX II and a compensatory action of NOS at M12. Conclusions: This HFD-induced neurogliovascular uncoupling pathway offers therapeutic targets to consider for improving cerebral vasoactive functions while preventing peripheral metabolic disturbances. Full article

Traumatic brain injury (TBI) is a major neurological condition affecting millions of individuals each year. Mild TBI (mTBI) manifests differently, with some individuals experiencing persistent, debilitating symptoms while others recover more rapidly. Despite its classification as “mild,” mTBI leads to both short- and long-term neurological effects, many of which occur due to functional changes in the brain. TBI-induced environmental changes within the brain play a critical role in shaping these functional outcomes. The importance of astrocytes in maintaining central nervous system (CNS) homeostasis has been increasingly recognized for their pivotal role in the brain’s response to TBI. Previous studies showed significant TBI-associated metabolic dysregulations. Therefore, we sought to analyze how astrocytes might adapt to persistent metabolic stressors in the post-injury microenvironment and identify injury-induced shifts occurring in vivo that may contribute to chronic metabolic dysfunction. We used an astrocyte-specific genome-scale metabolic model that allowed for the input of biologically relevant uptake rates corresponding to healthy astrocytes to analyze how the activity of metabolic pathways differed in hypoxic and acidic conditions. Additionally, these fluxes were integrated with mass spectrometry-based proteomics from male Sprague-Dawley rats subjected to mTBI to identify chronic adaptive neural responses post-injury. Comparison of modeled metabolic fluxes and experimental proteomic data demonstrated remarkable alignment, with both predicting significant changes in key metabolic processes including glycolysis, oxidative phosphorylation, the TCA cycle, and the Pentose Phosphate Pathway. These overlapping signatures may represent core survival strategies, offering insight into metabolic priorities and potentially serving as biomarkers of injury adaptation or recovery capacity. Full article

Chronic migraine (CM) is a debilitating neurological disorder, yet the glial-specific mechanisms underlying its pathophysiology in the trigeminal nucleus caudalis (TNC)—a critical hub for craniofacial pain processing—remain poorly understood. Here, we employed single-nucleus RNA sequencing (snRNA-seq) to resolve cell-type-specific transcriptional landscapes in a nitroglycerin (NTG)-induced CM rat model, with a particular focus on microglia and astrocytes. We identified 19 transcriptional clusters representing nine major cell types, among which reactive microglia (NTG-Mic) and astrocytes (NTG-Asts) were markedly expanded. The NTG-Mic displayed a glycolysis-dominant, complement-enriched state, whereas the NTG-Asts exhibited concurrent activation of amino acid transport and cytokine signaling pathways. Pseudotime trajectory analysis revealed bifurcated glial activation paths, with NTG driving both cell types toward terminal reactive states. Intercellular communication inference uncovered suppressed homeostatic interactions (e.g., CSF1-CSF1R) alongside enhanced proinflammatory signaling (e.g., FGF1-FGFR2, PTN-SDC4), particularly affecting neuron–glia and glia–glia crosstalk. Together, these findings define a high-resolution atlas of glial reprogramming in CM, implicating state-specific metabolic–immune transitions and dysregulated glial communication as potential targets for therapeutic intervention. Full article

A balanced excitatory/inhibitory (E/I) tone is crucial for proper brain function, and disruptions can lead to neurological disorders. This review explores the role of astrocytes in maintaining a balanced E/I tone in the brain, which is crucial for proper functioning. It highlights the potential for dysfunctional astrocyte metabolism to disrupt E/I balance, leading to neuronal dysfunction and potentially causing neurological disease pathogenesis. The review focuses on glucose, lactate shuttling, and glutamate metabolism. This review synthesizes findings from in vitro, in vivo, and human studies examining the interplay between astrocyte metabolism, neuronal activity, and E/I balance. Literature searches were conducted using keywords including “astrocyte metabolism”, “excitatory/inhibitory balance”, “glutamate”, “lactate shuttle”, “neurometabolic coupling”, and “neurological disorders” in databases such as PubMed and Web of Science. Disruptions in astrocyte glucose uptake or glycolysis can impair lactate production, reducing neuronal energy supply and affecting neuronal excitability. Impaired glutamate uptake and conversion to glutamine within astrocytes leads to elevated extracellular glutamate, promoting excitotoxicity. Altered glycogen metabolism and other metabolic impairments within astrocytes can also affect neuronal health and contribute to imbalances between excitation and inhibition. Dysfunctional astrocyte metabolism represents a significant contributor to E/I imbalance in the brain. Understanding the specific metabolic vulnerabilities of astrocytes and their impact on neuronal function provides potential therapeutic targets for neurological disorders characterized by E/I dysregulation. Targeting astrocyte metabolism may offer a novel approach to restoring E/I balance and improving neurological outcomes. Full article

The paraventricular nucleus of the hypothalamus (PVN) regulates, among others, the stress response, sexual behavior, and energy metabolism through its magnocellular and parvocellular neurosecretory cells. Within the PVN, ensemble coordination occurs through the many long-range synaptic afferents, whose activity in time relies on retrograde neuromodulation by, e.g., endocannabinoids. However, the nanoarchitecture of endocannabinoid signaling in the PVN, especially during neuronal development, remains undescribed. By using single-cell RNA sequencing, in situ hybridization, and immunohistochemistry during fetal and postnatal development in mice, we present a spatiotemporal map of both the 2-arachidonoylglycerol (2-AG) and anandamide (AEA) signaling cassettes, with a focus on receptors and metabolic enzymes, in both molecularly defined neurons and astrocytes. We find type 1 cannabinoid receptors (Cnr1), but neither Cnr2 nor Gpr55, expressed in neurons of the PVN. Dagla and Daglb, which encode the enzymes synthesizing 2-AG, were found in all neuronal subtypes of the PVN, with a developmental switch from Daglb to Dagla. Mgll, which encodes an enzyme degrading 2-AG, was only found sporadically. Napepld and Faah, encoding enzymes that synthesize and degrade AEA, respectively, were sparsely expressed in neurons throughout development. Notably, astrocytes expressed Mgll and both Dagl isoforms. In contrast, mRNA for any of the three major cannabinoid-receptor subtypes could not be detected. Immunohistochemistry validated mRNA expression and suggested that endocannabinoid signaling is configured to modulate the activity of afferent inputs, rather than local neurocircuits, in the PVN. Full article

Purinergic P2X receptors (P2X) are ATP-gated ion channels that are broadly expressed in the brain, particularly in the hypothalamus. As ionic channels with high permeability to calcium, P2X play an important and active role in neural functions. The hypothalamus contains a number of small nuclei with many molecularly defined types of peptidergic neurons that affect a wide range of physiological functions, including water balance, blood pressure, metabolism, food intake, circadian rhythm, childbirth and breastfeeding, growth, stress, body temperature, and multiple behaviors. P2X are expressed in hypothalamic neurons, astrocytes, tanycytes, and microvessels. This review focuses on cell-type specific expression of P2X in the most important hypothalamic nuclei, such as the supraoptic nucleus (SON), paraventricular nucleus (PVN), suprachiasmatic nucleus (SCN), anteroventral periventricular nucleus (AVPV), anterior hypothalamic nucleus (AHN), arcuate nucleus (ARC), ventromedial hypothalamic nucleus (VMH), dorsomedial hypothalamic nucleus (DMH), tuberomammillary nucleus (TMN), and lateral hypothalamic area (LHA).> The review also notes the possible role of P2X and extracellular ATP in specific hypothalamic functions. The literature summarized here shows that purinergic signaling is involved in the control of the hypothalamic-pituitary endocrine system, the hypothalamic–neurohypophysial system, the circadian systems and nonendocrine hypothalamic functions. Full article

Ever since the monocarboxylate, lactate, was shown to be more than a useless end-product of anaerobic glycolysis, the members of the brain energy metabolism research community are divided by two issues: First, could lactate replace glucose as the oxidative mitochondrial energy substrate? Second, should glycolysis continue to be divided into aerobic and anaerobic pathways? This opinion paper examined both the history and the reasons for this division and offered a unifying solution. Some readers may find this paper somewhat slanted, although many aspects of my opinion are backed, whenever possible, by data. Full article

Neurocysticercosis (NCC), a parasitic infection caused by Taenia solium larvae, remains a leading cause of acquired epilepsy worldwide, particularly in regions with inadequate sanitation and healthcare access. We present a case of NCC reactivation in a 64-year-old female who developed anomic aphasia—a rare manifestation of NCC—decades after her initial diagnosis. The patient’s clinical course was complicated by a potential trigger of semaglutide, which potentially attenuated the protective inflammatory response maintained by astrocytes and microglia, leading to the reactivation of dormant cysts. Brain imaging confirmed localized cystic changes, and treatment with antiparasitic agents and corticosteroids led to marked clinical improvement. This case highlights the complexity of NCC reactivation, highlighting the interplay of metabolic, immune, and parasitic factors. It emphasizes the need for vigilance in managing patients with dormant infections and investigating potential risks associated with novel therapeutic agents like GLP-1 receptor agonists. Further research is essential to unravel the mechanisms linking metabolic modulation to parasitic reactivation, offering insights into prevention and treatment strategies. Full article

Levodopa is the gold standard symptomatic treatment for Parkinson’s disease. Disease progression due to alpha-synuclein accumulation, brain inflammation, and the loss of dopamine neurons, as well as motor fluctuations, due to variations in levodopa plasma levels, remain a significant problem for Parkinson’s patients. Developing a therapeutic option that can simultaneously reduce the neuropathology associated with alpha-synuclein aggregation, attenuate oxidative stress and inflammation, and overcome variations in levodopa plasma levels is an unmet need to treat Parkinson’s disease. We determined the pharmacokinetics and pharmacodynamics of a small molecule, dubbed Pegasus, that conjugates dopamine with a nonantibiotic doxycycline derivative via a molecular linker. Mice harboring the human A53T mutation of alpha-synuclein or treated with MPTP were injected once daily with 50 mg/kg Pegasus for 2 weeks and assessed for motor, behavioral, and cognitive effects, followed by biochemical and histochemical analysis. Pegasus is a poor brain penetrant but it was metabolized to stable dopamine and tetracycline derivatives, and abundant plasma and brain levels of these metabolites were detected. Pegasus reduced soluble and insoluble alpha-synuclein levels, protected dopamine-producing neurons, and reduced astrocytic activation in A53T mice. Mice treated with Pegasus exhibited motor improvement (6.5 h) and reduction in anxiety-like behavior. Rotarod and grip strength improved in MPTP-treated mice when mice were treated with Pegasus or levodopa. Pegasus may be a multi-modal therapeutic option that can deliver stable dopamine into the CNS and reduce misfolded alpha-synuclein, activate dopamine receptors, and attenuate variations in dopamine levels. Full article

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. The 5-year survival rate has been estimated to be less than 20% while its incidence rates have more than tripled since the 1980s. Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) has been demonstrated to have an influential role in HCC progression and the development of an aggressive phenotype. AEG-1 has been shown to be upregulated in many cancers, including HCC. Studies have shown that it plays a crucial role in the proliferation, invasion and metastasis, and evasion of apoptosis in HCC. Its relationship with proteins and pathways, such as MYC, SND1, PI3K/AKT, and other signaling pathways demonstrates its pertinent role in oncogenic development and relevance as a biomarker and therapeutic target. Recent studies have shown that AEG-1 is present in tumor tissues, and the anti-AEG-1 antibody is detected in the blood of cancer patients, demonstrating its viability as a diagnostic/prognostic marker. This review paper shines light on recent findings regarding the molecular implications of AEG-1, with emphasis on its role of regulating metabolic dysfunction-associated steatohepatitis (MASH), a key predisposing factor for HCC, new treatment strategies targeting AEG-1, and challenges associated with analyzing this intriguing molecule. Full article