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TNFα prevents FGF4-mediated rescue of astrocyte dysfunction and reactivity in human ALS models.

Astrocytes play a crucial role in the onset and progression of amyotrophic lateral sclerosis (ALS), a fatal disorder marked by the degeneration of motor neurons (MNs) in the central nervous system. Although astrocytes in ALS are known to be toxic to MNs, the pathological changes leading to their neurotoxic phenotype remain poorly understood. In this study, we generated human astrocytes from induced pluripotent stem cells (iPSCs) carrying the ALS-associated A4V mutation in superoxide dismutase 1 (SOD1) to examine early cellular pathways and network changes. Proteomic analysis revealed that ALS …

Zinc signaling controls astrocyte-dependent synapse modulation via the PAF receptor pathway.

Astrocytes are important regulators of neuronal development and activity. Their activation plays a key role in the response to many central nervous system (CNS) pathologies. However, reactive astrocytes are a double-edged sword as their chronic or excessive activation may negatively impact CNS physiology, for example, via abnormal modulation of synaptogenesis and synapse function. Accordingly, astrocyte activation has been linked to neurodegenerative and neurodevelopmental disorders. Therefore, the attenuation of astrocyte activation may be an important approach for preventing and treating the…

Astrocytic Alterations and Dysfunction in Down Syndrome: Focus on Neurogenesis, Synaptogenesis, and Neural Circuits Formation.

Down syndrome (DS) is characterized by severe neurodevelopmental alterations that ultimately lead to the typical hallmark of DS: intellectual disability. In the DS brain, since the prenatal life stages, the number of astrocytes is disproportional compared to the healthy brain. This increase is due to a shift from neuron to astrocyte differentiation during brain development. Astrocytes are involved in numerous functions during brain development, including balancing pro-neurogenic and pro-gliogenic stimuli, sustaining synapse formation, regulating excitatory/inhibitory signal equilibrium, and su…

FXTAS Neuropathology Includes Widespread Reactive Astrogliosis and White Matter Specific Astrocyte Degeneration.

OBJECTIVE: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset progressive genetic neurodegenerative disorder that occurs in FMR1 premutation carriers. The temporal, spatial, and cell-type specific patterns of neurodegeneration in the FXTAS brain remain incompletely characterized. Intranuclear inclusion bodies are the neuropathological hallmark of FXTAS, which are largest and occur most frequently in astrocytes, glial cells that maintain brain homeostasis. Here, we characterized neuropathological alterations in astrocytes in multiple regions of the FXTAS brain. METHODS: Striat…

Mechanistic role of mesencephalic astrocyte-derived neurotrophic factor in myocardial ischemia/reperfusion injury.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a protein crucial for cellular stress response and survival, particularly in the nervous and cardiovascular systems. Unlike traditional neurotrophic factors, MANF primarily regulates endoplasmic reticulum (ER) stress and protects cells by reducing ER stress-induced apoptosis. MANF operates both inside and outside cells, influencing key pathways like JAK/STAT and NF-κB to enhance cell survival during stress. Beyond its neuroprotective role, MANF is also vital in cardiovascular protection, mitigating damage by reducing inflammation an

Астроцитизированный PTN уменьшает дефицит гиппокампального неврогенеза и когниции в моделях множественного склероза.

Множественный склероз (MS) — аутоиммунное воспалительное заболевание, которое приводит к моторным, сенсорным, когнитивным и эффективным расстройствам. Гиппокампальное обезвоживание, обычное явление в MS, связано с нарушенной когнитивной функцией и настроением. Несмотря на это, точные механизмы, лежащие в основе когнитивных нарушений в MS, по-прежнему остаются труднодостижимыми. Плейотропхин (PTN), скрытый нейронными стволовыми клетками и астроцитами, играет решающую роль в регулировании когниции. В этом исследовании изучается роль PTN на основе астроцитов. Мы обнаружили, что генетическое удале

Совпадение в аннотации оригинала
Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease that results in motor, sensory, cognitive, and affective deficit … g cognitive impairments in MS remain elusive. Pleiotrophin (PTN), secreted by neural stem cells and astrocytes, plays a crucial role in regulating cognition. This study investigates the role of astrocyte-derived PTN. We found that genetic deletion of astrocyte-derived PTN hinders hippocampal neurogenesis. Additionally, conditional ablation of PTN in astrocyt …

Astrocyte Signature in Alzheimer's Disease Continuum through a Multi-PET Tracer Imaging Perspective.

Reactive astrogliosis is an early event in the continuum of Alzheimer's disease (AD). Current advances in positron emission tomography (PET) imaging provide ways of assessing reactive astrogliosis in the living brain. In this review, we revisit clinical PET imaging and in vitro findings using the multi-tracer approach, and point out that reactive astrogliosis precedes the deposition of Aβ plaques, tau pathology, and neurodegeneration in AD. Furthermore, considering the current view of reactive astrogliosis heterogeneity-more than one subtype of astrocyte involved-in AD, we discuss how astrocyt

Role of astrocyte senescence regulated by the non- canonical autophagy in the neuroinflammation associated to cerebral malaria.

BACKGROUND: Cerebral malaria (CM) is a fatal neuroinflammatory syndrome caused (in humans) by the protozoa Plasmodium (P.) falciparum. Glial cell activation is one of the mechanisms that contributes to neuroinflammation in CM. RESULT: By studying a mouse model of CM (caused by P. berghei ANKA), we describe that the induction of autophagy promoted p21-dependent senescence in astrocytes and that CXCL-10 was part of the senescence-associated secretory phenotype. Furthermore, p21 expression was observed in post-mortem brain and peripheral blood samples from patients with CM. Lastly, we found that…

A defined roadmap of radial glia and astrocyte differentiation from human pluripotent stem cells.

Human gliogenesis remains poorly understood, and derivation of astrocytes from human pluripotent stem cells (hPSCs) is inefficient and cumbersome. Here, we report controlled glial differentiation from hPSCs that bypasses neurogenesis, which otherwise precedes astrogliogenesis during brain development and in vitro differentiation. hPSCs were first differentiated into radial glial cells (RGCs) resembling resident RGCs of the fetal telencephalon, and modulation of specific cell signaling pathways resulted in direct and stepwise induction of key astroglial markers (NFIA, NFIB, SOX9, CD44, S100B, g…

Neuronal and astrocytic contributions to Huntington's disease dissected with zinc finger protein transcriptional repressors.

Huntington's disease (HD) is caused by expanded CAG repeats in the huntingtin gene (HTT) resulting in expression of mutant HTT proteins (mHTT) with extended polyglutamine tracts, including in striatal neurons and astrocytes. It is unknown whether pathophysiology in vivo can be attenuated by lowering mHTT in either cell type throughout the brain, and the relative contributions of neurons and astrocytes to HD remain undefined. We use zinc finger protein (ZFP) transcriptional repressors to cell-selectively lower mHTT in vivo. Astrocytes display loss of essential functions such as cholesterol meta…

Promotion of astrocyte-neuron glutamate-glutamine shuttle by SCFA contributes to the alleviation of Alzheimer's disease.

The brain is particularly susceptible to oxidative damage which is a key feature of several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease. The shuttling of glutathione (GSH) precursors from astrocytes to neurons has been shown to be instrumental for the neuroprotective activity. Here, we revealed that short chain fatty acids (SCFA), which have been related to AD and PD, could promote glutamate-glutamine shuttle to potentially resist oxidative damage in neurons at cellular level. Furthermore, we performed nine-month-long dietar…

An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis.

Cholesterol is an essential membrane structural component and steroid hormone precursor, and is involved in numerous signaling processes. Astrocytes regulate brain cholesterol homeostasis and they supply cholesterol to the needs of neurons. ATP-binding cassette transporter A1 (ABCA1) is the main cholesterol efflux transporter in astrocytes. Here we show dysregulated cholesterol homeostasis in astrocytes generated from human induced pluripotent stem cells (iPSCs) derived from males with fragile X syndrome (FXS), which is the most common cause of inherited intellectual disability. ABCA1 levels a…

Dysregulation of astrocyte-secreted pleiotrophin contributes to neuronal structural and functional deficits in Down Syndrome.

Neuronal dendrite patterning and synapse formation are tightly regulated during development to promote proper connectivity. Astrocyte-secreted proteins act as guidance and pro-synaptogenic factors during development, but little is known about how astrocytes may contribute to neurodevelopmental disorders. Here we identify down-regulation of the astrocyte-secreted molecule pleiotrophin as a major contributor to neuronal morphological alterations in the Ts65Dn mouse model of Down Syndrome. We find overlapping deficits in neuronal dendrites, spines and intracortical synapses in Ts65Dn mutant and p…

Astrocyte senescence-like response related to peripheral nerve injury-induced neuropathic pain.

BACKGROUND: Peripheral nerve damage causes neuroinflammation, which plays a critical role in establishing and maintaining neuropathic pain ( … sponse in the spinal cord. Lipopolysaccharide (LPS) was administered to induce senescence of spinal astrocytes in primary cultures in vitro, to explore the potential impacts of senescence on the secretion of proinflammatory factors. Furthermore, single-cell RNA sequencing (scRNA-seq) was conducted to identify senescence-related molecular responses in spinal …

The neuroinflammatory astrocytic P2X7 receptor: Alzheimer's disease, ischemic brain injury, and epileptic state.

INTRODUCTION: Astrocytes have previously been considered as cells supporting neuronal functions, but they are now recognized as active players in maintaining central nervous system (CNS) homeostasis. Astrocytes can communicate with other CNS cells, i.e. through the gliotransmitter ATP and P2X7 receptors (Rs). AREAS COVERED: In this review, we will discuss how the P2X7R initiates the release of gliotransmitters and proinflammatory cytokines/chemokines, thereby establishing a dialog between astrocytes and neurons and, in addition, causing neuroinflammation. In astrocytes, dysregulation of P2X7R…

Disrupting astrocyte-neuron lactate transport prevents cocaine seeking after prolonged withdrawal.

Energy supply, especially the transfer of lactate from astrocytes to neurons, is critical for neuronal plasticity. However, its role in the incubation of cocaine craving remains largely unknown. Using an extended-access self-administration model and in vivo 1H-magnetic resonance spectroscopy, we found that lactate synthesis in the central amygdala (CeA) is required for the intensified cocaine craving after prolonged withdrawal. Furthermore, incubated cocaine seeking was associated with a selective increase in monocarboxylate transporter 2 (MCT2) and MCT4 expression levels. Down-regulation of a…

Overexpression of UCP4 in astrocytic mitochondria prevents multilevel dysfunctions in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is becoming increasingly prevalent worldwide. It represents one of the greatest medical challenges as no pharmacologic treatments are available to prevent disease progression. Astrocytes play crucial functions within neuronal circuits by providing metabolic and functional support, regulating interstitial solute composition, and modulating synaptic transmission. In addition to these physiological functions, growing evidence points to an essential role of astrocytes in neurodegenerative diseases like AD. Early-stage AD is associated with hypometabolism and oxidative stre…

Subtle vascular and astrocytic changes in the brain of coronavirus disease 2019 (COVID-19) patients.

BACKGROUND AND PURPOSE: In the central nervous system, a multitude of changes have been described associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, such as microglial activation, perivascular lymphocyte cuffing, hypoxic-ischaemic changes, microthrombosis, infarcts or haemorrhages. It was sought here to assess the vascular basement membranes (vBMs) and surrounding perivascular astrocytes for any morphological changes in acute respiratory syndrome (coronavirus disease 2019, COVID-19) patients. METHODS: The light microscopy morphology of the vBMs and perivas…

Cutaneous burn injury induces neuroinflammation and reactive astrocyte activation in the hippocampus of aged mice.

BACKGROUND: By 2050, one in six people globally will be 65 or older. Confusion and delirium are significant complications after burn injury, especially in the elderly population. The etiology is still unknown, however complications may be driven by pro-inflammatory activation of astrocytes within the hippocampus (HPC) after burn injury. Reduced levels of phosphorylated cyclic-AMP response binding element (pCREB), caused by elevated systemic pro-inflammatory cytokines, could lead to cognitive decline and memory impairment. METHODS: To examine the effects of remote injury on neuroinflammation i…

Astrocyte-specific loss of lactoferrin influences neuronal structure and function by interfering with cholesterol synthesis.

Growing evidence indicates that circulating lactoferrin (Lf) is implicated in peripheral cholesterol metabolism disorders. It has emerged that the distribution of Lf changes in astrocytes of aging brains and those exhibiting neurodegeneration; however, its physiological and/or pathological role remains unknown. Here, we demonstrate that astrocyte-specific knockout of Lf (designated cKO) led to decreased body weight and cognitive abnormalities during early life in mice. Accordingly, there was a reduction in neuronal outgrowth and synaptic structure in cKO mice. Importantly, Lf deficiency in the…