Reactive astrocyte nomenclature, definitions, and future directions

Nature Neuroscience, Journal Year: 2021, Volume and Issue: 24(3), P. 312 - 325

Published: Feb. 15, 2021

Language: Английский

---

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

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Oct. 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.

Language: Английский

---

iPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders

Cell stem cell, Journal Year: 2022, Volume and Issue: 29(2), P. 189 - 208

Published: Feb. 1, 2022

Language: Английский

---

Inflammation in multiple sclerosis: consequences for remyelination and disease progression

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(5), P. 305 - 320

Published: April 14, 2023

Language: Английский

---

Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease

Brain, Journal Year: 2019, Volume and Issue: 143(1), P. 266 - 288

Published: Nov. 5, 2019

Abstract Huntington’s disease is associated with a reactive microglial response and consequent inflammation. To address the role of these cells in pathogenesis, we depleted microglia from R6/2 mice, rapidly progressing model marked by behavioural impairment, mutant huntingtin (mHTT) accumulation, early death, through colony-stimulating factor 1 receptor inhibition (CSF1Ri) pexidartinib (PLX3397) for duration disease. Although observed an interferon gene signature addition to downregulated neuritogenic synaptic pathways disease, overt inflammation was not evident morphology or cytokine transcript levels mice. Nonetheless, CSF1Ri-induced elimination reduced prevented disease-related grip strength object recognition deficits, mHTT astrogliosis, striatal volume loss, latter which reductions cell number but extracellular accumulation chondroitin sulphate proteoglycans (CSPGs)—a primary component glial scars. A concurrent loss proteoglycan-containing perineuronal nets also only this strikingly increased brains naïve littermates, suggesting new as homeostatic regulators net formation integrity.

Language: Английский

---

Intrinsic mutant HTT-mediated defects in oligodendroglia cause myelination deficits and behavioral abnormalities in Huntington disease

Proceedings of the National Academy of Sciences, Journal Year: 2019, Volume and Issue: 116(19), P. 9622 - 9627

Published: April 23, 2019

White matter abnormalities are a nearly universal pathological feature of neurodegenerative disorders including Huntington disease (HD). A long-held assumption is that this white pathology simply secondary outcome the progressive neuronal loss manifests with advancing disease. Using mouse model HD, here we show and myelination an early appearing before manifestation any behavioral or loss. We further selective inactivation mutant huntingtin (mHTT) in NG2+ oligodendrocyte progenitor cell population prevented myelin certain deficits HD mice. Strikingly, improvements outcomes were seen despite continued expression mHTT nonoligodendroglial cells neurons, astrocytes, microglia. RNA-seq ChIP-seq analyses, implicate pathogenic mechanism involves enhancement polycomb repressive complex 2 (PRC2) activity by intrinsic oligodendroglial dysfunction observed HD. Our findings challenge dogma regarding etiology highlight contribution epigenetic mechanisms to dysfunction. results suggest ameliorating may be beneficial for

Language: Английский

---

The contribution of glial cells to Huntington's disease pathogenesis

Neurobiology of Disease, Journal Year: 2020, Volume and Issue: 143, P. 104963 - 104963

Published: June 25, 2020

Glial cells play critical roles in the normal development and function of neural circuits, but many neurodegenerative diseases, they become dysregulated may contribute to brain pathology. In Huntington's disease (HD), glial both lose functions gain neuropathic phenotypes. addition, cell-autonomous dysfunction elicited by mutant huntingtin (mHTT) expression specific cell types is sufficient induce pathology disease-related impairments motor cognitive performance, suggesting that these drive certain aspects pathogenesis. support this imaging studies pre-symptomatic HD patients work on mouse models have suggested occurs at a very early stage disease, prior onset deficits. Furthermore, selectively ablating mHTT from or correcting for HD-induced changes their transcriptional profile rescues some HD-related phenotypes, demonstrating potential targeting therapeutic intervention. Here we review emerging research focused understanding involvement different This providing new insight into how impacts biological healthy as well induced might change way integrate circuits.

Language: Английский

---

Human and mouse cortical astrocytes: a comparative view from development to morphological and functional characterization

Frontiers in Neuroanatomy, Journal Year: 2023, Volume and Issue: 17

Published: April 17, 2023

The vision of astroglia as a bare scaffold to neuronal circuitry has been largely overturned. Astrocytes exert neurotrophic function, but also take active part in supporting synaptic transmission and calibrating blood circulation. Many aspects their functioning have unveiled from studies conducted murine models, however evidence is showing many differences between mouse human astrocytes starting development encompassing morphological, transcriptomic physiological variations when they achieve complete maturation. evolutionary race toward superior cognitive abilities unique humans drastically impacted neocortex structure and, together with circuitry, affected the acquisition species-specific properties. In this review, we summarize diversities astroglia, specific focus on neocortex, panoramic view that starts developmental origin include all structural molecular mark uniqueness astrocytes.

Language: Английский

---

Astrocytes as master modulators of neural networks: Synaptic functions and disease‐associated dysfunction of astrocytes

Annals of the New York Academy of Sciences, Journal Year: 2023, Volume and Issue: 1525(1), P. 41 - 60

Published: May 23, 2023

Abstract Astrocytes are the most abundant glial cell type in central nervous system and essential to development, plasticity, maintenance of neural circuits. heterogeneous, with their diversity rooted developmental programs modulated by local brain environment. play integral roles regulating coordinating activity extending far beyond metabolic support neurons other phenotypes. Both gray white matter astrocytes occupy critical functional niches capable modulating physiology on time scales slower than synaptic but faster those adaptive responses requiring a structural change or myelination. Given many associations roles, it is not surprising that astrocytic dysfunction has been causally implicated broad set neurodegenerative neuropsychiatric disorders. In this review, we focus recent discoveries concerning contributions function networks, dual contribution development maturation, role supporting myelin integrity, hence conduction its regulation. We then address emerging disease pathogenesis potential strategies for targeting these cells therapeutic purposes.

Language: Английский

---

Young glial progenitor cells competitively replace aged and diseased human glia in the adult chimeric mouse brain

Nature Biotechnology, Journal Year: 2023, Volume and Issue: 42(5), P. 719 - 730

Published: July 17, 2023

Abstract Competition among adult brain cells has not been extensively researched. To investigate whether healthy glia can outcompete diseased human in the forebrain, we engrafted wild-type (WT) glial progenitor (hGPCs) produced from embryonic stem into striata of mice that had neonatally chimerized with mutant Huntingtin ( mHTT )-expressing hGPCs. The WT hGPCs outcompeted and ultimately eliminated their Huntington’s disease (HD) counterparts, repopulating host glia. Single-cell RNA sequencing revealed acquired a YAP1/MYC/E2F-defined dominant competitor phenotype upon interaction HD also older resident isogenic transplanted neonatally, suggesting competitive success depended primarily on relative ages competing populations, rather than presence . These data indicate aged may be broadly replaced by younger hGPCs, therapeutic strategy for replacement

Language: Английский

---