Diverse signaling mechanisms and heterogeneity of astrocyte reactivity in Alzheimer's disease.

Alzheimer's disease (AD) affects various brain cell types, including astrocytes, which are the most abundant cell types in the central nervous system (CNS). Astrocytes not only provide homeostatic support to neurons but also actively regulate synaptic signaling and functions and become reactive in response to CNS insults through diverse signaling pathways including the JAK/STAT, NF-κB, and GPCR-elicited pathways. The advent of new technology for transcriptomic profiling at the single-cell level has led to increasing recognition of the highly versatile nature of reactive astrocytes and the context-dependent specificity of astrocyte reactivity. In AD, reactive astrocytes have long been observed in senile plaques and have recently been suggested to play a role in AD pathogenesis and progression. However, the precise contributions of reactive astrocytes to AD remain elusive, and targeting this complex cell population for AD treatment poses significant challenges. In this review, we summarize the current understanding of astrocyte reactivity and its role in AD, with a particular focus on the signaling pathways that promote astrocyte reactivity and the heterogeneity of reactive astrocytes. Furthermore, we explore potential implications for the development of therapeutics for AD. Our objective is to shed light on the complex involvement of astrocytes in AD and offer insights into potential therapeutic targets and strategies for treating and managing this devastating neurodegenerative disorder.

Palmitic Acid Upregulates Type I Interferon-Mediated Antiviral Response and Cholesterol Biosynthesis in Human Astrocytes.

Chronic intake of a high-fat diet increases saturated fatty acids in the brain causing the progression of neurodegenerative diseases. Palmitic acid is a free fatty acid abundant in the diet that at high concentrations may penetrate the blood-brain barrier and stimulate the production of pro-inflammatory cytokines, leading to inflammation in astrocytes. The use of the synthetic neurosteroid tibolone in protection against fatty acid toxicity is emerging, but its transcriptional effects on palmitic acid-induced lipotoxicity remain unclear. Herein, we performed a transcriptome profiling of normal human astrocytes to investigate the molecular mechanisms by which palmitic acid causes cellular damage to astrocytes, and whether tibolone could reverse its detrimental effects. Astrocytes undergo a profound transcriptional change at 2 mM palmitic acid, affecting the expression of 739 genes, 366 upregulated and 373 downregulated. However, tibolone at 10 nM does not entirely reverse palmitic acid effects. Additionally, the protein-protein interaction reveals two novel gene clustering modules. The first module involves astrocyte defense responses by upregulation of pathways associated with antiviral innate immunity, and the second is linked to lipid metabolism. Our data suggest that activation of viral response signaling pathways might be so far, the initial molecular mechanism of astrocytes in response to a lipotoxic insult by palmitic acid, triggered particularly upon increased expression levels of IFIT2, IRF1, and XAF1. Therefore, this novel approach using a global gene expression analysis may shed light on the pleiotropic effects of palmitic acid on astrocytes, and provide a basis for future studies addressed to elucidate these responses in neurodegenerative conditions, which is highly valuable for the design of therapeutic strategies.

Urokinase-Type Plasminogen Activator Triggers Wingless/Int1-Independent Phosphorylation of the Low-Density Lipoprotein Receptor-Related Protein-6 in Cerebral Cortical Neurons.

BACKGROUND: Urokinase-type plasminogen activator (uPA) is a serine proteinase found in excitatory synapses located in the II/III and V cortical layers. The synaptic release of uPA promotes the formation of synaptic contacts and the repair of synapses damaged by various forms of injury, and its abundance is decreased in the synapse of Alzheimer's disease (AD) patients. Inactivation of the Wingless/Int1 (Wnt)-ß-catenin pathway plays a central role in the pathogenesis of AD. Soluble amyloid-ß (Aß) prevents the phosphorylation of the low-density lipoprotein receptor-related protein-6 (LRP6), and the resultant inactivation of the Wnt-ß-catenin pathway prompts the amyloidogenic processing of the amyloid-ß protein precursor (AßPP) and causes synaptic loss. OBJECTIVE: To study the role of neuronal uPA in the pathogenesis of AD. METHODS: We used in vitro cultures of murine cerebral cortical neurons, a murine neuroblastoma cell line transfected with the APP-695 Swedish mutation (N2asw), and mice deficient on either plasminogen, or uPA, or its receptor (uPAR). RESULTS: We show that uPA activates the Wnt-ß-catenin pathway in cerebral cortical neurons by triggering the phosphorylation of LRP6 via a plasmin-independent mechanism that does not require binding of Wnt ligands (Wnts). Our data indicate that uPA-induced activation of the Wnt-ß-catenin pathway protects the synapse from the harmful effects of soluble Aß and prevents the amyloidogenic processing of AßPP by inhibiting the expression of ß-secretase 1 (BACE1) and the ensuing generation of Aß40 and Aß42 peptides. CONCLUSION: uPA protects the synapse and antagonizes the inhibitory effect of soluble Aß on the Wnt-ß-catenin pathway by providing an alternative pathway for LRP6 phosphorylation and ß-catenin stabilization.

Metabolomic Analysis of Human Astrocytes in Lipotoxic Condition: Potential Biomarker Identification by Machine Learning Modeling.

The association between neurodegenerative diseases (NDs) and obesity has been well studied in recent years. Obesity is a syndrome of multifactorial etiology characterized by an excessive accumulation and release of fatty acids (FA) in adipose and non-adipose tissue. An excess of FA generates a metabolic condition known as lipotoxicity, which triggers pathological cellular and molecular responses, causing dysregulation of homeostasis and a decrease in cell viability. This condition is a hallmark of NDs, and astrocytes are particularly sensitive to it, given their crucial role in energy production and oxidative stress management in the brain. However, analyzing cellular mechanisms associated with these conditions represents a challenge. In this regard, metabolomics is an approach that allows biochemical analysis from the comprehensive perspective of cell physiology. This technique allows cellular metabolic profiles to be determined in different biological contexts, such as those of NDs and specific metabolic insults, including lipotoxicity. Since data provided by metabolomics can be complex and difficult to interpret, alternative data analysis techniques such as machine learning (ML) have grown exponentially in areas related to omics data. Here, we developed an ML model yielding a 93% area under the receiving operating characteristic (ROC) curve, with sensibility and specificity values of 80% and 93%, respectively. This study aimed to analyze the metabolomic profiles of human astrocytes under lipotoxic conditions to provide powerful insights, such as potential biomarkers for scenarios of lipotoxicity induced by palmitic acid (PA). In this work, we propose that dysregulation in seleno-amino acid metabolism, urea cycle, and glutamate metabolism pathways are major triggers in astrocyte lipotoxic scenarios, while increased metabolites such as alanine, adenosine, and glutamate are suggested as potential biomarkers, which, to our knowledge, have not been identified in human astrocytes and are proposed as candidates for further research and validation.

Tibolone Pre-Treatment Ameliorates the Dysregulation of Protein Translation and Transport Generated by Palmitic Acid-Induced Lipotoxicity in Human Astrocytes: A Label-Free MS-Based Proteomics and Network Analysis.

Excessive accumulation and release of fatty acids (FAs) in adipose and non-adipose tissue are characteristic of obesity and are associated with the leading causes of death worldwide. Chronic exposure to high concentrations of FAs such as palmitic acid (pal) is a risk factor for developing different neurodegenerative diseases (NDs) through several mechanisms. In the brain, astrocytic dysregulation plays an essential role in detrimental processes like metabolic inflammatory state, oxidative stress, endoplasmic reticulum stress, and autophagy impairment. Evidence shows that tibolone, a synthetic steroid, induces neuroprotective effects, but its molecular mechanisms upon exposure to pal remain largely unknown. Due to the capacity of identifying changes in the whole data-set of proteins and their interaction allowing a deeper understanding, we used a proteomic approach on normal human astrocytes under supraphysiological levels of pal as a model to induce cytotoxicity, finding changes of expression in proteins related to translation, transport, autophagy, and apoptosis. Additionally, tibolone pre-treatment showed protective effects by restoring those same pal-altered processes and increasing the expression of proteins from cell survival processes. Interestingly, ARF3 and IPO7 were identified as relevant proteins, presenting a high weight in the protein-protein interaction network and significant differences in expression levels. These proteins are related to transport and translation processes, and their expression was restored by tibolone. This work suggests that the damage caused by pal in astrocytes simultaneously involves different mechanisms that the tibolone can partially revert, making tibolone interesting for further research to understand how to modulate these damages.

Integrated Metabolomics and Lipidomics Reveal High Accumulation of Glycerophospholipids in Human Astrocytes under the Lipotoxic Effect of Palmitic Acid and Tibolone Protection.

Lipotoxicity is a metabolic condition resulting from the accumulation of free fatty acids in non-adipose tissues which involves a series of pathological responses triggered after chronic exposure to high levels of fatty acids, severely detrimental to cellular homeostasis and viability. In brain, lipotoxicity affects both neurons and other cell types, notably astrocytes, leading to neurodegenerative processes, such as Alzheimer (AD) and Parkinson diseases (PD). In this study, we performed for the first time, a whole lipidomic characterization of Normal Human Astrocytes cultures exposed to toxic concentrations of palmitic acid and the protective compound tibolone, to establish and identify the set of potential metabolites that are modulated under these experimental treatments. The study covered 3843 features involved in the exo- and endo-metabolome extracts obtained from astrocytes with the mentioned treatments. Through multivariate statistical analysis such as PCA (principal component analysis), partial least squares (PLS-DA), clustering analysis, and machine learning enrichment analysis, it was possible to determine the specific metabolites that were affected by palmitic acid insult, such as phosphoethanolamines, phosphoserines phosphocholines and glycerophosphocholines, with their respective metabolic pathways impact. Moreover, our results suggest the importance of tibolone in the generation of neuroprotective metabolites by astrocytes and may be relevant to the development of neurodegenerative processes.

Tissue-type plasminogen activator induces TNF-α-mediated preconditioning of the blood-brain barrier.

Ischemic tolerance is a phenomenon whereby transient exposure to a non-injurious preconditioning stimulus triggers resistance to a subsequent lethal ischemic insult. Despite the fact that not only neurons but also astrocytes and endothelial cells have a unique response to preconditioning stimuli, current research has been focused mostly on the effect of preconditioning on neuronal death. Thus, it is unclear if the blood-brain barrier (BBB) can be preconditioned independently of an effect on neuronal survival. The release of tissue-type plasminogen activator (tPA) from perivascular astrocytes in response to an ischemic insult increases the permeability of the BBB. In line with these observations, treatment with recombinant tPA increases the permeability of the BBB and genetic deficiency of tPA attenuates the development of post-ischemic edema. Here we show that tPA induces ischemic tolerance in the BBB independently of an effect on neuronal survival. We found that tPA renders the BBB resistant to an ischemic injury by inducing TNF-α-mediated astrocytic activation and increasing the abundance of aquaporin-4-immunoreactive astrocytic end-feet processes in the neurovascular unit. This is a new role for tPA, that does not require plasmin generation, and with potential therapeutic implications for patients with cerebrovascular disease.

The Emerging Role of Long Non-Coding RNAs and MicroRNAs in Neurodegenerative Diseases: A Perspective of Machine Learning.

Neurodegenerative diseases (NDs) are characterized by progressive neuronal dysfunction and death of brain cells population. As the early manifestations of NDs are similar, their symptoms are difficult to distinguish, making the timely detection and discrimination of each neurodegenerative disorder a priority. Several investigations have revealed the importance of microRNAs and long non-coding RNAs in neurodevelopment, brain function, maturation, and neuronal activity, as well as its dysregulation involved in many types of neurological diseases. Therefore, the expression pattern of these molecules in the different NDs have gained significant attention to improve the diagnostic and treatment at earlier stages. In this sense, we gather the different microRNAs and long non-coding RNAs that have been reported as dysregulated in each disorder. Since there are a vast number of non-coding RNAs altered in NDs, some sort of synthesis, filtering and organization method should be applied to extract the most relevant information. Hence, machine learning is considered as an important tool for this purpose since it can classify expression profiles of non-coding RNAs between healthy and sick people. Therefore, we deepen in this branch of computer science, its different methods, and its meaningful application in the diagnosis of NDs from the dysregulated non-coding RNAs. In addition, we demonstrate the relevance of machine learning in NDs from the description of different investigations that showed an accuracy between 85% to 95% in the detection of the disease with this tool. All of these denote that artificial intelligence could be an excellent alternative to help the clinical diagnosis and facilitate the identification diseases in early stages based on non-coding RNAs.

Urokinase-type plasminogen activator-mediated crosstalk between N-cadherin and ß-catenin promotes wound healing.

Urokinase-type plasminogen activator (uPA; encoded by Plau) is a serine proteinase that, in the central nervous system, induces astrocytic activation. ß-Catenin is a protein that links the cytoplasmic tail of cadherins to the actin cytoskeleton, thus securing the formation of cadherin-mediated cell adhesion complexes. Disruption of cell-cell contacts leads to the detachment of ß-catenin from cadherins, and ß-catenin is then degraded by the proteasome following its phosphorylation by GSK3ß. Here, we show that astrocytes release uPA following a scratch injury, and that this uPA promotes wound healing via a plasminogen-independent mechanism. We found that uPA induces the detachment of ß-catenin from the cytoplasmic tail of N-cadherin (NCAD; also known as CDH2) by triggering its phosphorylation at Tyr654. Surprisingly, this is not followed by degradation of ß-catenin because uPA also induces the phosphorylation of the low density lipoprotein receptor-related protein 6 (LRP6) at Ser1490, which then blocks the kinase activity of GSK3ß. Our work indicates that the ensuing cytoplasmic accumulation of ß-catenin is followed by its nuclear translocation and ß-catenin-triggered transcription of the receptor for uPA (Plaur), which in turn is required for uPA to induce astrocytic wound healing.

Plasminogen Activators in Neurovascular and Neurodegenerative Disorders.

The neurovascular unit (NVU) is a dynamic structure assembled by endothelial cells surrounded by a basement membrane, pericytes, astrocytes, microglia and neurons. A carefully coordinated interplay between these cellular and non-cellular components is required to maintain normal neuronal function, and in line with these observations, a growing body of evidence has linked NVU dysfunction to neurodegeneration. Plasminogen activators catalyze the conversion of the zymogen plasminogen into the two-chain protease plasmin, which in turn triggers a plethora of physiological events including wound healing, angiogenesis, cell migration and inflammation. The last four decades of research have revealed that the two mammalian plasminogen activators, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), are pivotal regulators of NVU function during physiological and pathological conditions. Here, we will review the most relevant data on their expression and function in the NVU and their role in neurovascular and neurodegenerative disorders.

Brain lipidomics as a rising field in neurodegenerative contexts: Perspectives with Machine Learning approaches.

Lipids are essential for cellular functioning considering their role in membrane composition, signaling, and energy metabolism. The brain is the second most abundant organ in terms of lipid concentration and diversity only after adipose tissue. However, in the central system (CNS) lipid dysregulation has been linked to the etiology, progression, and severity of neurodegenerative diseases such as Alzheimers, Parkinson, and Multiple Sclerosis. Advances in the human genome and subsequent sequencing technologies allowed us the study of lipidomics as a promising approach to diagnosis and treatment of neurodegeneration. Lipidomics advances rapidly increased the amount and quality of data allowing the integration with other omic types as well as implementing novel bioinformatic and quantitative tools such as machine learning (ML). Integration of lipidomics data with ML, as a powerful quantitative predictive approach, led to improvements in diagnostic biomarker prediction, clinical data integration, network, and systems approaches for neural behavior, novel etiology markers for inflammation, and neurodegeneration progression and even Mass Spectrometry image analysis. In this sense, by exploiting lipidomics data with ML is possible to improve the identification of new biomarkers or unveil new molecular mechanisms associated with lipid impairment across neurodegeneration. In this review, we present the lipidomic neurobiology state-of-the-art highlighting its potential applications to study neurodegenerative conditions. Also, we present theoretical background, applications, and advances in the integration of lipidomics with ML. This review opens the door to new approaches in this rising field.

Advances in Astrocyte Computational Models: From Metabolic Reconstructions to Multi-omic Approaches.

The growing importance of astrocytes in the field of neuroscience has led to a greater number of computational models devoted to the study of astrocytic functions and their metabolic interactions with neurons. The modeling of these interactions demands a combined understanding of brain physiology and the development of computational frameworks based on genomic-scale reconstructions, system biology, and dynamic models. These computational approaches have helped to highlight the neuroprotective mechanisms triggered by astrocytes and other glial cells, both under normal conditions and during neurodegenerative processes. In the present review, we evaluate some of the most relevant models of astrocyte metabolism, including genome-scale reconstructions and astrocyte-neuron interactions developed in the last few years. Additionally, we discuss novel strategies from the multi-omics perspective and computational models of other glial cell types that will increase our knowledge in brain metabolism and its association with neurodegenerative diseases.

Tibolone Ameliorates the Lipotoxic Effect of Palmitic Acid in Normal Human Astrocytes.

Lipotoxicity is a pathological condition resulting from the excessive accumulation of fatty acids, like palmitic acid (PA), within the cell. This pathological phenomenon induces deleterious metabolic changes in cells and is associated with neurodegenerative diseases, dyslipidemia, and obesity. Recent evidence has demonstrated that tibolone, a synthetic steroid, protects cellular damage through various mechanisms; but its underlying actions upon lipotoxic damage are unknown. In this study, we assessed the effects of tibolone administration on normal human astrocytes subject to supraphysiological levels of palmitic acid as a model to induce cytotoxicity. Our results demonstrated that tibolone attenuated lipotoxic damage of PA in normal human astrocytes by reducing PI uptake in 53%, prevented cardiolipin loss by 17%, reduced fragmented/condensed nuclei by 50.81% and attenuated the production of superoxide ions by around 20%. In conclusion, these data suggest that protective effects of tibolone against lipotoxicity may be mediated, in part, through modulation of the different cellular mechanisms of astrocytes.

Effects of estrogens and androgens on mitochondria under normal and pathological conditions.

Several lines of evidence have suggested that mitochondrial dysfunction plays a key role in neurodegeneration. The mitochondrial function is a potential target for steroid hormones, which could exert protective activities in the brain and other tissues. The decrease of some sex steroids with aging has been associated with deleterious effects on brain function and progression to neurodegenerative diseases. Recent in vitro and in vivo evidence provides the basis for this review on the interplay of sex steroids and mitochondrial defects in preventing or improving pathological events in the central nervous system (CNS). In this article, the role of mitochondria under normal and pathological states will be discussed. In addition, we will review studies conducted on steroidal compounds, which have neuroprotective effects targeting mitochondria. It has been shown that these compounds could exert both direct and indirect effects on mitochondria that promote or preserve mitochondrial function under pathological circumstances, such as acute brain injury and chronic neurodegeneration.

Multiple Pathways Involved in Palmitic Acid-Induced Toxicity: A System Biology Approach.

Inflammation is a complex biological response to injuries, metabolic disorders or infections. In the brain, astrocytes play an important role in the inflammatory processes during neurodegenerative diseases. Recent studies have shown that the increase of free saturated fatty acids such as palmitic acid produces a metabolic inflammatory response in astrocytes generally associated with damaging mechanisms such as oxidative stress, endoplasmic reticulum stress, and autophagic defects. In this aspect, the synthetic neurosteroid tibolone has shown to exert protective functions against inflammation in neuronal experimental models without the tumorigenic effects exerted by sexual hormones such as estradiol and progesterone. However, there is little information regarding the specific mechanisms of tibolone in astrocytes during inflammatory insults. In the present study, we performed a genome-scale metabolic reconstruction of astrocytes that was used to study astrocytic response during an inflammatory insult by palmitate through Flux Balance Analysis methods and data mining. In this aspect, we assessed the metabolic fluxes of human astrocytes under three different scenarios: healthy (normal conditions), induced inflammation by palmitate, and tibolone treatment under palmitate inflammation. Our results suggest that tibolone reduces the L-glutamate-mediated neurotoxicity in astrocytes through the modulation of several metabolic pathways involved in glutamate uptake. We also identified a set of reactions associated with the protective effects of tibolone, including the upregulation of taurine metabolism, gluconeogenesis, cPPAR and the modulation of calcium signaling pathways. In conclusion, the different scenarios studied in our model allowed us to identify several metabolic fluxes perturbed under an inflammatory response and the protective mechanisms exerted by tibolone.

Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury.

Traumatic brain injury (TBI) is a serious public health problem. It may result in severe neurological disabilities and in a variety of cellular metabolic alterations for which available therapeutic strategies are limited. In the last decade, the use of estrogenic compounds, which activate protective mechanisms in astrocytes, has been explored as a potential experimental therapeutic approach. Previous works have suggested estradiol (E2) as a neuroprotective hormone that acts in the brain by binding to estrogen receptors (ERs). Several steroidal and nonsteroidal estrogenic compounds can imitate the effects of estradiol on ERs. These include hormonal estrogens, phytoestrogens and synthetic estrogens, such as selective ER modulators or tibolone. Current evidence of the role of astrocytes in mediating protective actions of estrogenic compounds after TBI is reviewed in this paper. We conclude that the use of estrogenic compounds to modulate astrocytic properties is a promising therapeutic approach for the treatment of TBI.

Astrocytes and endoplasmic reticulum stress: A bridge between obesity and neurodegenerative diseases.

Endoplasmic reticulum (ER) is a subcellular organelle involved in protein folding and processing. ER stress constitutes a cellular process characterized by accumulation of misfolded proteins, impaired lipid metabolism and induction of inflammatory responses. ER stress has been suggested to be involved in several human pathologies, including neurodegenerative diseases and obesity. Different studies have shown that both neurodegenerative diseases and obesity trigger similar cellular responses to ER stress. Moreover, both diseases are assessed in astrocytes as evidences suggest these cells as key regulators of brain homeostasis. However, the exact contributions to the effects of ER stress in astrocytes in the various neurodegenerative diseases and its relation with obesity are not well known. Here, we discuss recent advances in the understanding of molecular mechanisms that regulate ER stress-related disorders in astrocytes such as obesity and neurodegeneration. Moreover, we outline the correlation between the activated proteins of the unfolded protein response (UPR) in these pathological conditions in order to identify possible therapeutic targets for ER stress in astrocytes. We show that ER stress in astrocytes shares UPR activation pathways during both obesity and neurodegenerative diseases, demonstrating that UPR related proteins like ER chaperone GRP 78/Bip, PERK pathway and other exogenous molecules ameliorate UPR response and promote neuroprotection.

Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network.

Astrocytes are the most abundant cells of the central nervous system; they have a predominant role in maintaining brain metabolism. In this sense, abnormal metabolic states have been found in different neuropathological diseases. Determination of metabolic states of astrocytes is difficult to model using current experimental approaches given the high number of reactions and metabolites present. Thus, genome-scale metabolic networks derived from transcriptomic data can be used as a framework to elucidate how astrocytes modulate human brain metabolic states during normal conditions and in neurodegenerative diseases. We performed a Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network with the purpose of elucidating a significant portion of the metabolic map of the astrocyte. This is the first global high-quality, manually curated metabolic reconstruction network of a human astrocyte. It includes 5,007 metabolites and 5,659 reactions distributed among 8 cell compartments, (extracellular, cytoplasm, mitochondria, endoplasmic reticle, Golgi apparatus, lysosome, peroxisome and nucleus). Using the reconstructed network, the metabolic capabilities of human astrocytes were calculated and compared both in normal and ischemic conditions. We identified reactions activated in these two states, which can be useful for understanding the astrocytic pathways that are affected during brain disease. Additionally, we also showed that the obtained flux distributions in the model, are in accordance with literature-based findings. Up to date, this is the most complete representation of the human astrocyte in terms of inclusion of genes, proteins, reactions and metabolic pathways, being a useful guide for in-silico analysis of several metabolic behaviors of the astrocyte during normal and pathologic states.

Relationship Between Obesity, Alzheimer's Disease, and Parkinson's Disease: an Astrocentric View.

Obesity is considered one of the greatest risk to human health and is associated with several factors including genetic components, diet, and physical inactivity. Recently, the relationship between obesity and numerous progressive and aging-related neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD) have been observed. Thus, the involvement of the most abundant and heterogeneous group of glial cells in neurodegenerative diseases, the astrocytes, is caused by a combination of the failure on their normal homeostatic functions and the increase of toxic metabolites upon pathological event. Upon brain damage, molecular signals induce astrocyte activation and migration to the site of injury, entering in a highly active state, with the aim to contribute to ameliorating or worsening the pathology. In this regard, the aim of this review is to elucidate the relationship between obesity, Alzheimer's disease, and Parkinson's disease and highlight the role of astrocytes in these pathologies.