Search Results (134)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tau tangles, chronic neuroinflammation, and synaptic loss, leading to cognitive decline. Extracellular vesicles (EVs)—lipid bilayer nanoparticles secreted by nearly all cell types—have emerged as critical mediators of intercellular communication, playing a complex dual role in both the pathogenesis and potential treatment of AD. This review generally delineates two opposite roles of EVs in pathogenesis and potential treatment of AD. On one hand, EVs derived from neurons, astrocytes, microglia and oligodendrocytes can propagate toxic proteins (Aβ, tau) and inflammatory signals, thereby accelerating disease progression. On the other hand, EVs—especially those from mesenchymal stem cells (MSCs)—exert neuroprotective effects by facilitating toxic protein clearance, modulating immune responses, preserving synaptic integrity, and alleviating oxidative stress. The cargo-carrying function of EVs gives them considerable diagnostic value. The associated cargos such as proteins and microRNAs (miRNAs) in the EVs may serve as minimally invasive biomarkers for early detection and monitoring of AD. Therapeutically, engineered EVs, including those incorporating CRISPR/Cas9-based genetic modification, are being developed as sophisticated delivery platforms for targeting core AD pathologies. Furthermore, this review highlights emerging technologies such as microfluidic chips and focused ultrasound (FUS), discussing their potential to enhance the translational prospects of EV-based early diagnostic and treatment for AD. Full article

This review examines convergent neurobiological mechanisms linking stress and drugs that drive stress-induced drug-related behaviors. It first outlines the main theoretical frameworks explaining substance use disorders (SUDs), emphasizing vulnerability factors—particularly stressful life events—that increase addiction risk. The analysis integrates preclinical evidence demonstrating that chronic stress facilitates cross-sensitization to psychostimulants and accelerates drug self-administration, underscoring how stress and drugs converge on glutamatergic and dopaminergic transmission within the Nucleus Accumbens (NAc). Special attention is given to the glial cells, particularly microglia and astrocytes, in mediating stress-induced neuroimmune activation and glutamate dysregulation in the NAc. Three major themes related to microglia–astrocyte crosstalk are addressed: (i) the contribution of these glial cells to neuroimmune and glutamatergic alterations induced by stress; (ii) their role in synaptic and structural plasticity changes within the NAc; and (iii) the mechanisms by which stress and drug exposure reshape glial–neuronal communication, driving the comorbidity between stress and SUDs. A dedicated section focuses on key neuroimmune signaling pathways—particularly the TNF-α/NF-κB axis—and their involvement in stress-induced vulnerability to cocaine addiction. Finally, the review discusses preclinical evidence supporting the therapeutic potential of repurposed glutamate-modulating agents as promising pharmacological candidates for treating comorbid stress and cocaine-use disorder. Full article

Synapses, abundant in the brain, are structures needed for life. Our Introduction, based on the forms of such structures published few decades ago, helped in developing recent concepts of health and diseases. Growing axons govern their growth by cell-to-cell communication, axon guidance, and synapse orientations. The assembly of synapses requires the organization and function of pre-synaptic and post-synaptic neuronal terminals with a liquid–liquid phase, governed by Ca²⁺ responses of thin astrocyte domains. Upon synapse stimulation, the clefts expand up to several folds while pre- and post-synaptic thickness remains unchanged. In additional responses, neurons co-operate with astrocytes and extracellular vesicles (EVs), the latter dependent on extracellular and intracellular spaces. Astrocyte and microglia cells and/or EV secretions induce neurons by various effects including traveling changes. Pre-synaptic responses are defined as canonical if based on neurotransmitter release; non-canonical if they are without release and are discharged by EVs, not neurotransmitters. Health and diseases depend on other general properties, such as those defined molecularly. Among neurodegenerative diseases, attention is specified by various properties of Alzheimer’s and other diagnoses. Critical identifications can be due to astrocyte and microglia cells or multiple effects induced by EVs. At present, the complexity of therapies, although of limited success, is developing innovative initiatives. Full article

Parkinson’s disease (PD) is a neurodegenerative pathology defined by specific, distinctive signs, primarily the progressive loss of dopaminergic neurons (DAergic) in the substantia nigra pars compacta (SNpc), associated with gliosis phenomena. The mechanisms that trigger the degeneration of DAergic neurons are not yet fully elucidated, although it is recognized that the interaction between genetic and environmental factors acts as a critical modulator of neuronal vulnerability. Strong evidence points to glial reactivity as a central element in PD pathophysiology; however, it remains a controversial topic whether this activation has a protective effect or, on the contrary, whether it contributes to exacerbating DAergic neuronal loss. The use of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)—a neurotoxic substance—represented a turning point in Parkinson’s research, allowing the clarification of various molecular mechanisms of the disease. The primary aim of this review is to explore the current state of knowledge regarding the role of astrocytes in the processes of DAergic neurodegeneration, neuroprotection, and neurorepair. We focused on the relationship between astrocytic origin factors and neurogenic signals that mediate MPTP-induced plasticity in DAergic neurons of the nigrostriatal system. The contribution of reactive astrocytes in promoting DAergic neurogenesis starting from Neural Stem/Progenitor Cells (NPCs) present in the adult midbrain is also analyzed. Among the mediators released by astrocytes, we have previously identified the Wnt/β-catenin signaling pathway as a fundamental element capable of positively influencing neuroplasticity and dopaminergic neuronal repair induced by the toxic MPTP. In conclusion, deciphering the intrinsic plasticity of nigrostriatal DAergic neurons and signals that facilitate communication between astrocytes and NPCs is crucial for the identification of potential therapeutic targets aimed at stimulating neuronal repair. Full article

Astrocytes play a key role in maintaining redox balance and supporting neuronal survival within the central nervous system (CNS). Their antioxidant machinery, primarily involving the Nrf2–ARE (nuclear factor erythroid 2-related factor 2–antioxidant response element) pathway, glutathione (GSH) metabolism, and mitochondrial function, enables the removal of reactive oxygen and nitrogen species (ROS and RNS) and supports neuronal resistance to oxidative stress. Effective communication between neurons and astrocytes coordinates metabolic and antioxidative responses via glutamate-, nitric oxide-, and calcium-dependent signalling. Disruption of this crosstalk during traumatic injury, ischemia, or neurodegenerative disease causes redox imbalance, neuroinflammation, and excitotoxicity, which contribute to progressive neurodegeneration. Astrocytic Nrf2 activation reduces oxidative damage and inflammation, while its suppression encourages a neurotoxic glial phenotype. Current evidence emphasizes various therapeutic strategies targeting astrocytic redox mechanisms, including small-molecule Nrf2 activators, GSH precursors, mitochondria-targeted antioxidants (MTAs), and RNA- and gene-based approaches. These interventions boost the antioxidant ability of astrocytes, influence reactive cell phenotypes, and support neuronal recovery in preclinical models. Although there are still challenges in delivery and safety, restoring neuron–glia redox signalling offers a promising strategy for neuroprotective treatments aimed at reducing oxidative stress-related CNS injury and disease progression. Full article

Astrocytic calcium signaling is a central mechanism of neuron-glia communication that operates across multiple spatial and temporal scales. Traditionally, research has focused on intracellular Ca²⁺ oscillations that regulate gliotransmitter release, ion homeostasis, and metabolic support. Recent evidence, however, reveals that extracellular calcium ([Ca²⁺]o) is not a passive reservoir but a dynamic signaling mediator capable of influencing neuronal excitability within milliseconds. Through mechanisms such as calcium-sensing receptor (CaSR) activation, ion channel modulation, surface charge effects, and ephaptic coupling, astrocytes emerge as active partners in both slow and rapid modes of communication. This dual perspective reshapes our understanding of brain physiology and disease. Disrupted Ca²⁺ signaling contributes to network instability in epilepsy, synaptic dysfunction in Alzheimer’s and Parkinson’s disease, and impaired maturation in neurodevelopmental disorders. Methodological advances, including Ca²⁺-selective microelectrodes, genetically encoded extracellular indicators, and computational modeling, are beginning to uncover the richness of extracellular Ca²⁺ dynamics, though challenges remain in achieving sufficient spatial and temporal resolution. By integrating classical intracellular pathways with emerging insights into extracellular signaling, this review highlights astrocytes as central architects of the ionic landscape. Recognizing calcium as both an intracellular messenger and an extracellular signaling mediator provides a unifying framework for neuron–glia interactions and opens new avenues for therapeutic intervention. Full article

Obesity causes millions of deaths each year due to metabolic complications, making it a major public health challenge. It results from a chronic imbalance between caloric intake and energy expenditure. Among central structures regulating energy balance, the dorsal vagal complex (DVC) integrates metabolic signals from energy stores and the gastrointestinal tract and coordinates autonomic responses. While historically overshadowed by a focus on neurons, the role of glial cells in regulating energy balance is now well established. Connexin 43 (Cx43) is a well-known protein expressed by astrocytes, playing a key role in glial and neuroglial communication. To investigate the role of astrocytic Cx43 within the DVC, where its expression is remarkably high, we specifically reduced it using an RNA interference approach. Although reduced Cx43 expression led to modified astrocyte and microglia morphology and phenotype, our analyses did not reveal significant changes in the animal’s metabolic phenotype under standard feeding conditions as well as under a high-fat, high-sugar diet. These results suggest that denser astrocytic tiling and hyper-ramified microglia may constitute a buffering system that preserves metabolic and autonomic outputs when a single connexin pathway fails. Full article

Tenascin-C (TNC) is a complex extracellular matrix (ECM) protein that plays a critical role in regulating cellular adhesion, motility, proliferation, and inflammation through its interaction with Toll-like receptor 4 (TLR4) and other receptors. The upregulation of TNC is associated with inflammatory responses, autoimmune disorders, and neoplastic conditions during both physiological and pathological tissue remodeling. In the central nervous system (CNS), TNC contributes to neuroinflammatory processes by modulating the function of immune cells and the secretion of pro-inflammatory mediators, thereby playing a pivotal role in the initiation and progression of neuroinflammatory diseases. TNC is expressed in astrocytes, neural progenitor cells, and various neuronal populations within both developing and mature CNS regions. It regulates neuronal migration and axonal guidance during neurogenesis, facilitating synaptic plasticity and CNS regeneration. Furthermore, TNC enhances neuroplasticity through interactions with receptor families, such as integrins, to establish the molecular connections necessary for cell communication and signal transduction. This review investigates the mechanistic properties of TNC, focusing on its spatiotemporal expression, molecular interactions with receptors, and its role in neurological disorders, in addition to its modulatory capacity in neuroplastic processes. Additionally, this review delves into recent research advancements with respect to neuroinflammation involving TNC, along with therapeutic strategies targeting TNC. Full article

Astrocytes, the principal components of astroglia, play essential roles in maintaining neuronal and synaptic homeostasis in the central nervous system. By regulating extracellular levels of glutamate, potassium (K⁺), and calcium (Ca²⁺), they prevent excitotoxicity and support neuronal survival. Astrocytes also modulate synaptic transmission and plasticity through gliotransmission, including vesicular glutamate release and D-serine synthesis via the serine shuttle, which regulates NMDA receptor activity. They provide metabolic support by facilitating glucose and oxygen transport from the vasculature, forming dynamic neurovascular units. Through signaling pathways such as cAMP-PKA and interactions with neurotrophic factors like BDNF and GDNF, astrocytes influence gene expression, synaptic remodeling, and plasticity. Furthermore, astrocytes exhibit regional and functional heterogeneity, which underlies their diverse contributions to both physiological and pathological conditions, including neurodegenerative diseases. This review summarizes current knowledge on astrocytic regulation of neuronal homeostasis, synaptic plasticity, and metabolism, highlighting their mechanisms of network communication, gliotransmission, and regional specialization, and discusses their implications in health and disease. Full article

Fear memory is a critical adaptive process that enables organisms to avoid potential threats and survive in complex environments. Traditionally viewed as a neuronal phenomenon, emerging evidence has demonstrated that astrocytes play a fundamental role in fear memory acquisition, consolidation, extinction, and retrieval across the distributed neural network encompassing the amygdala, hippocampus, and prefrontal cortex. This review presents recent advances in our understanding of the molecular mechanisms by which astrocytes modulate fear memory processing within the tripartite circuit. We examine how astrocytes contribute to synaptic plasticity, neurotransmitter regulation, metabolic support, and intercellular communication during the different phases of fear memory processing. Particular emphasis is placed on the region-specific functions of astrocytes, their dynamic interactions with neurons, and their therapeutic implications for treating fear-related disorders such as post-traumatic stress disorder (PTSD) and anxiety disorders. The integration of cutting-edge technologies, including spatial transcriptomics, optogenetics, and chemogenetics, has revealed sophisticated astrocyte–neuron communication mechanisms that challenge the traditional neuron-centric view of memory processing. Full article

Traumatic brain injury (TBI) is one of the most common forms of neurotrauma, accompanied by significant disruptions in neuronal homeostasis and intercellular communication. A key protein involved in these processes is connexin 43 (Cx43), which facilitates the formation of gap junctions in the astrocytic network. In this study, using confocal and immunofluorescence microscopy, ultrastructural analysis, and molecular modeling, we investigated the dynamics of Cx43 expression and structural changes in neuroglia during various post-traumatic periods following TBI. It was shown that in the acute phase, 24 h post-injury, there is a reduction in Cx43 expression, accompanied by apoptotic neuronal degradation, disruption of nuclear NeuN localization, and destruction of cellular ultrastructure. By 7 days post-injury, a significant increase in Cx43 levels was observed, along with the formation of protein aggregates associated with pronounced reactive astrogliosis. Peripheral blood analysis revealed persistent neutrophilia, lymphopenia, and reduced monocyte levels, reflecting a systemic inflammatory response and immunosuppression, which was corroborated by a custom-trained neural network-based computer vision model. Linear regression and correlation analyses further identified a strong positive association between normalized monocyte levels and Cx43 expression, a moderate negative correlation with lymphocytes, and no significant correlation with neutrophils. Using a custom-built computer vision model, we confirmed these hematological trends and detected subtle changes, such as early increases in platelet counts, that were not captured by manual evaluation. The model demonstrated strong performance in classifying common blood cell types and proved to be a valuable tool for monitoring dynamic post-traumatic shifts in blood. Molecular dynamics modeling of Cx43 identified a pH-dependent mechanism of conformational reorganization under post-traumatic acidosis, mediated by the interaction between protonated His142 and Glu103. This mechanism mimics the structural consequences of the pathogenic E103K mutation and may play a critical role in the neurotoxic effects of Cx43 in TBI. These findings highlight the complexity of Cx43 regulation under traumatic conditions and its potential significance as a target for neuroprotective therapy. Full article

AMOG/β₂, the β₂ isoform of the sodium pump (Na⁺/K⁺-ATPase), functions as an adhesion molecule on glial cells, mediating critical neuron–astrocyte interactions during central nervous system (CNS) development. Despite its established role in glial adhesion, the neuronal receptor that partners with AMOG/β₂ remains unknown. This review examines the structural and functional properties of AMOG/β₂, including its capacity to form trans-dimers, both homophilic and potentially heterophilic—drawing comparisons with the β₁ subunit, a well-characterized adhesion molecule. By integrating computational modeling, in vitro data, and structural predictions, we explore how factors such as N-glycosylation and cis-membrane interactions influence β₂-mediated adhesion. We further consider candidate neuronal partners, including TSPAN31 and RTN4, and speculate on their potential roles in mediating heterophilic AMOG/β₂ interactions. Finally, we discuss the broader implications of AMOG/β₂ in neuron–glia communication, synaptic organization, neurodevelopment, and CNS disorders such as glioblastoma. Identifying the binding partner of AMOG/β₂ holds promise not only for understanding the molecular basis of CNS adhesion but also for uncovering novel mechanisms of neuroglial regulation in health and disease. Full article

Autophagy is a fundamental catabolic pathway critical for maintaining cellular homeostasis in the central nervous system (CNS). While neuronal autophagy has been extensively studied, growing evidence highlights the crucial roles of astrocytic autophagy in CNS physiology and pathology. Astrocytes regulate metabolic support, redox balance, and neuroinflammatory responses. These functions are closely linked to autophagic activity. The disruption of astrocytic autophagy contributes to synaptic dysfunction, chronic inflammation, myelin impairment, and blood–brain barrier instability. Dysregulation of astrocytic autophagy has been implicated in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. This review summarizes the molecular mechanisms of autophagy in astrocytes and delineates its role in intercellular communication with neurons, microglia, oligodendrocytes, and endothelial cells. Furthermore, we will discuss current pharmacological approaches targeting astrocytic autophagy, with particular attention to repurposed agents such as rapamycin, lithium, and caloric restriction mimetics. Although promising in preclinical models, therapeutic translation is challenged by the complexity of autophagy’s dual roles and cell-type specificity. A deeper understanding of astrocytic autophagy and its crosstalk with other CNS cell types may facilitate the development of targeted interventions for neurodegenerative diseases. Full article

Brain pathophysiology in Down syndrome (DS), the most common genetic cause of intellectual disability, has traditionally been considered a consequence of neuronal dysfunction. However, although it is well documented that astrocytes play a critical role in brain homeostasis, synaptic regulation, and neuronal support, and their malfunction has been associated with the onset and progression of different neurological disorders, only a few studies have addressed whether astrocyte dysfunction can contribute to the DS pathophysiology. Astrocytes are increased in number and size, and show increased levels of expression of astroglial markers like S100β and GFAP. In this study, we detected a region-specific increase in astrocyte population in CA1 and, to a lesser extent, in the dentate gyrus. Single-nucleus transcriptomic profiling identified markers associated with reactive astroglia, synaptic transmission, and neuroinflammation in trisomic astrocytes. Functional analysis revealed abnormal Ca²⁺ oscillations in trisomic astrocytes and impaired astrocyte-to-neuron communication in CA1, the most affected subregion, leading to astrocyte-mediated excitatory synaptic depression. Our findings demonstrate that astrocytes play an active and critical role in the pathophysiology of DS, not only as reactive responders to neuronal injury but as key contributors to the disease process itself. This astrocytic dysfunction presents a region-specific distribution within the hippocampus, suggesting localized vulnerability and complex glial involvement in DS-related neuropathology. Full article

CD44, a structurally diverse cell-surface glycoprotein, plays a multifaceted and indispensable role in neural tissue across both physiological and pathological conditions. It orchestrates complex cell–extracellular matrix interactions and intracellular signaling through its variant isoforms and post-translational modifications and is broadly expressed in neural stem/progenitor cells, microglia, astrocytes, and selected neuronal populations. The interactions of CD44 with ligands such as hyaluronan and osteopontin regulate critical cellular functions, including migration, differentiation, inflammation, and synaptic plasticity. In microglia and macrophages, CD44 mediates immune signaling and phagocytic activity, and it is dynamically upregulated in neuroinflammatory diseases, particularly through pathways involving Toll-like receptor 4. CD44 expression in astrocytes is abundant during central nervous system development and in diseases, contributing to glial differentiation, reactive astrogliosis, and scar formation. Though its expression is less prominent in mature neurons, CD44 supports neural plasticity, circuit organization, and injury-induced repair mechanisms. Additionally, its expression at nervous system barriers, such as the blood–brain barrier, underscores its role in regulating vascular permeability during inflammation and ischemia. Collectively, CD44 emerges as a critical integrator of neural cell function and intercellular communication. Although the roles of CD44 in glial cells appear to be similar to those explored in other tissues, the expression of this molecule and its variants on neurons reveals peculiar functions. Elucidating the cell-type-specific roles and regulation of CD44 variants may offer novel therapeutic strategies for diverse neurological disorders. Full article