Astrocytes in human central nervous system diseases: a frontier for new therapies

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Окт. 13, 2023

Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence the central nervous system (CNS). contribute pathophysiology all neurological neuropsychiatric disorders in ways that can be either beneficial or detrimental disorder outcome. Pathophysiological changes astroglia primary secondary result gain loss functions. respond external, non-cell autonomous signals associated with any form CNS pathology by undergoing complex variable their structure, molecular expression, function. In addition, internally driven, cell astroglial innate properties lead pathologies. Astroglial is complex, different pathophysiological states phenotypes context-specific vary disorder, disorder-stage, comorbidities, age, sex. Here, we classify into (i) reactive astrogliosis, (ii) atrophy function, (iii) degeneration death, (iv) astrocytopathies characterised aberrant forms drive disease. We review across spectrum human diseases disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack epilepsy, as well neurodevelopmental, neurodegenerative, metabolic disorders. Characterising cellular mechanisms represents new frontier identify novel therapeutic strategies.

Язык: Английский

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Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones

Biomolecules, Год журнала: 2024, Номер 14(3), С. 305 - 305

Опубликована: Март 4, 2024

The majority of approved therapies for many diseases are developed to target their underlying pathophysiology. Understanding disease pathophysiology has thus proven vital the successful development clinically useful medications. Stroke is generally accepted as leading cause adult disability globally and ischemic stroke accounts most common form two main types. Despite its health socioeconomic burden, there still minimal availability effective pharmacological treatment. In this review, we take an in-depth look at etiology stroke, including molecular cellular changes. This followed by a highlight drugs, therapies, complementary medicines that or undergoing clinical trials treatment management stroke. We also identify unexplored potential targets in pathogenesis can be exploited increase pool anti-stroke neuroprotective agents through de novo drug repurposing.

Язык: Английский

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Brain stars take the lead during critical periods of early postnatal brain development: relevance of astrocytes in health and mental disorders

Molecular Psychiatry, Год журнала: 2024, Номер 29(9), С. 2821 - 2833

Опубликована: Март 29, 2024

In the brain, astrocytes regulate shape and functions of synaptic vascular compartments through a variety released factors membrane-bound proteins. An imbalanced astrocyte activity can therefore have drastic negative impacts on brain development, leading to onset severe pathologies. Clinical pre-clinical studies show alterations in cell number, morphology, molecular makeup astrocyte-dependent processes different affected regions neurodevelopmental (ND) neuropsychiatric (NP) disorders. Astrocytes proliferate, differentiate mature during critical period early postnatal time window elevated glia-dependent regulation proper balance between synapse formation/elimination, which is pivotal refining connectivity. Therefore, any intrinsic and/or extrinsic altering these may result an aberrant remodeling mental The peculiar bridging position further allows them "compute" state consequently secrete bloodstream, serve as diagnostic biomarkers distinct healthy or disease conditions. Here, we collect recent advancements regarding astrogenesis astrocyte-mediated neuronal network periods focusing elimination. We then propose alternative hypotheses for involvement aberrancies ND NP light well-known differential prevalence certain disorders males females, also discuss putative sex-dependent influences events. From translational perspective, understanding age- astrocyte-specific functional changes help identify cellular (dys)functions health disease, favouring development tools selection tailored treatment options male/female patients.

Язык: Английский

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Glaucoma: from pathogenic mechanisms to retinal glial cell response to damage

Frontiers in Cellular Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Янв. 25, 2024

Glaucoma is a neurodegenerative disease of the retina characterized by irreversible loss retinal ganglion cells (RGCs) leading to visual loss. Degeneration RGCs and their axons, as well damage remodeling lamina cribrosa are main events in pathogenesis glaucoma. Different molecular pathways involved RGC death, which triggered exacerbated consequence number risk factors such elevated intraocular pressure (IOP), age, ocular biomechanics, or low perfusion pressure. Increased IOP one most important associated with this pathology only for treatment currently available, nevertheless, on many cases progression continues, despite control. Thus, elevation not trigger glaucomatous damage, showing evidence that other can induce death pathology, would be advance neurodegeneration. The underlying mechanisms driving process glaucoma include ischemia/hypoxia, mitochondrial dysfunction, oxidative stress neuroinflammation. In glaucoma, like disorders, immune system immunoregulation conducted mainly glial cells, microglia, astrocytes, Müller cells. increase produces activation tissue. Chronic may provoke proinflammatory state at level inducing blood barrier disruption death. modulation response constitute an interesting new approach

Язык: Английский

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Brain clearance of protein aggregates: a close-up on astrocytes

Molecular Neurodegeneration, Год журнала: 2024, Номер 19(1)

Опубликована: Янв. 16, 2024

Abstract Protein misfolding and accumulation defines a prevailing feature of many neurodegenerative disorders, finally resulting in the formation toxic intra- extracellular aggregates. Intracellular aggregates can enter space be subsequently transferred among different cell types, thus spreading between connected brain districts. Although microglia perform predominant role removal aggregated proteins, mounting evidence suggests that astrocytes actively contribute to clearing process. However, molecular mechanisms used by remove misfolded proteins are still largely unknown. Here we first provide brief overview progressive transition from soluble monomers insoluble fibrils characterizes amyloid referring α-Synuclein Tau as archetypical examples. We then highlight at basis astrocyte-mediated clearance with focus on their potential ability recognize, collect, internalize digest protein Finally, explore targeting future therapeutic approach for treatment disorders characterized accumulation.

Язык: Английский

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Phagocytic astrocytes: Emerging from the shadows of microglia

Glia, Год журнала: 2022, Номер 70(6), С. 1009 - 1026

Опубликована: Фев. 10, 2022

Abstract Elimination of dead or live cells take place in both a healthy and diseased central nervous system (CNS). Dying are quickly cleared by phagocytosis for the maintenance CNS recovery after injury. Live parts thereof, such as synapses myelin, appropriately eliminated to maintain refine neural networks during development adulthood. Microglia, specific population resident macrophages CNS, classically considered primary phagocytes; however, astrocytes have also been highlighted phagocytes last decade. Phagocytic targets receptors reported be mostly common between microglia, which raises question how astrocytic differs from microglial phagocytosis, these two phagocytic systems cooperate. In this review, we address consequences particularly focusing on elusive points.

Язык: Английский

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Astrocyte regulation of synaptic signaling in psychiatric disorders

Neuropsychopharmacology, Год журнала: 2022, Номер 48(1), С. 21 - 36

Опубликована: Май 16, 2022

Язык: Английский

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The roles of microglia and astrocytes in myelin phagocytosis in the central nervous system

Journal of Cerebral Blood Flow & Metabolism, Год журнала: 2022, Номер 43(3), С. 325 - 340

Опубликована: Ноя. 2, 2022

Myelination is an important process in the central nervous system (CNS). Oligodendrocytes (OLs) extend multiple layers to densely sheath on axons, composing myelin achieve efficient electrical signal conduction. The myelination during developmental stage maintains a balanced state. However, numerous CNS diseases including neurodegenerative and cerebrovascular cause demyelination disrupt homeostasis, resulting inflammation white matter deficits. Effective clearance of debris needed region demyelination, which key step for remyelination tissue regeneration. Microglia astrocytes are major resident phagocytic cells brain, may play different or collaborative roles myelination. participate through engulfing excessive unneeded myelin. They also involved degenerated accelerating remyelination, healthy inhibiting remyelination. This review focuses microglia phagocytosing brain diseased brain. In addition, interaction between mediate engulfment summarized.

Язык: Английский

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Microglial diversity in neuropathic pain

Trends in Neurosciences, Год журнала: 2023, Номер 46(7), С. 597 - 610

Опубликована: Май 25, 2023

Язык: Английский

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Antibody-Mediated Clearance of Brain Amyloid-β: Mechanisms of Action, Effects of Natural and Monoclonal Anti-Aβ Antibodies, and Downstream Effects

Journal of Alzheimer s Disease Reports, Год журнала: 2023, Номер 7(1), С. 873 - 899

Опубликована: Авг. 7, 2023

Immunotherapeutic efforts to slow the clinical progression of Alzheimer’s disease (AD) by lowering brain amyloid-β (Aβ) have included Aβ vaccination, intravenous immunoglobulin (IVIG) products, and anti-Aβ monoclonal antibodies. Neither vaccination nor IVIG slowed progression. Despite conflicting phase III results, antibody Aducanumab received Food Drug Administration (FDA) approval for treatment AD in June 2021. The only treatments unequivocally demonstrated date are antibodies Lecanemab Donanemab. FDA January 2023 based on II results showing PET-detectable Aβ; released at that time indicated slowing Topline May Donanemab’s trial revealed primary secondary end points had been met. Antibody binding facilitates its clearance from via multiple mechanisms including promoting microglial phagocytosis, activating complement, dissolving fibrillar Aβ, antibody-Aβ complexes blood-brain barrier receptors. peripheral blood may also promote cerebral efflux a sink mechanism. According amyloid hypothesis, targeting progression, it must decrease downstream neuropathological processes tau aggregation phosphorylation (possibly) inflammation oxidative stress. This review discusses antibody-mediated clearance, findings trials involving IVIG, antibodies, effects reported those trials, approaches which might improve Aβ-clearing ability

Язык: Английский

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