Impact Of Astrocytes Research Articles

Parkinson\u2019s Disease\u2013Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance

Parkinson’s disease (PD) is a neurodegenerative, progressive disease without a cure. To prevent PD onset or at least limit neurodegeneration, a better understanding of the underlying cellular and molecular disease mechanisms is crucial. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent one of the most common causes of familial PD. In addition, LRRK2 variants are risk factors for sporadic PD, making LRRK2 an attractive therapeutic target. Mutations in LRRK2 have been linked to impaired alpha-synuclein (α-syn) degradation in neurons. However, in which way pathogenic LRRK2 affects α-syn clearance by astrocytes, the major glial cell type of the brain, remains unclear. The impact of astrocytes on PD progression has received more attention and recent data indicate that astrocytes play a key role in α-syn-mediated pathology. In the present study, we aimed to compare the capacity of wild-type astrocytes and astrocytes carrying the PD-linked G2019S mutation in Lrrk2 to ingest and degrade fibrillary α-syn. For this purpose, we used two different astrocyte culture systems that were exposed to sonicated α-syn for 24 h and analyzed directly after the α-syn pulse or 6 days later. To elucidate the impact of LRRK2 on α-syn clearance, we performed various analyses, including complementary imaging, transmission electron microscopy, and proteomic approaches. Our results show that astrocytes carrying the G2019S mutation in Lrrk2 exhibit a decreased capacity to internalize and degrade fibrillar α-syn via the endo-lysosomal pathway. In addition, we demonstrate that the reduction of α-syn internalization in the Lrrk2 G2019S astrocytes is linked to annexin A2 (AnxA2) loss of function. Together, our findings reveal that astrocytic LRRK2 contributes to the clearance of extracellular α-syn aggregates through an AnxA2-dependent mechanism.

Abstract 4847: Investigating the impact of astrocytes on targeted therapy of melanoma brain metastases

Abstract Metastatic melanoma is a devastating disease that leads to the development of brain metastases (MBMs) in 40-60% of patients. Upon diagnosis of brain metastases, patient overall survival is less than 6 months. Poor patient survival is believed to be due to resistance driven by the brain microenvironment. Collectively, these findings underscore the need for novel therapeutic strategies to improve the survival of patients with MBMs. Development of effective therapies relies on an understanding of the interaction between MBMs and different cell types within the brain microenvironment. Astrocytes are the most abundant cell type within the brain and interact with MBMs through direct and indirect mechanisms. Astrocyte interaction with MBMs alters MBM gene expression and promotes metastatic outgrowth and resistance to cytotoxic chemotherapies. Exactly how astrocytes alter MBM response to MAPK inhibition remains unclear. Using conditioned media from primary astrocytes, as well as co-culture of primary astrocytes with either the MBM cell line WM4265-2 or the primary melanoma cell line WM983B, we found that the interaction of melanoma cells with astrocytes increased melanoma sensitivity to MEK inhibition (MEKi). RNA sequencing of WM4265-2 and WM983B cell lines treated with the MEK inhibitor PD0325901 (PD901) showed significant up-regulation of the transcriptional regulator ID3, which is known to play a role in the resistance of melanoma to MAPK inhibition. Interestingly, astrocyte conditioned media prevented the upregulation of ID3. To validate this finding, we silenced ID3 in WM4265-2 and WM983B cell lines, and showed that knockdown of ID3 caused increased sensitivity to MEKi. These combined data support the premise that the increased response to PD901 in MBMs exposed to astrocytes is due to ID3 down-regulation. How ID3 modulates resistance to MAPK inhibition remains unclear. Elucidating the mechanism of ID3 mediated resistance to MEKi may uncover new avenues for improving the treatment of melanoma brain metastases. Citation Format: Joshua Parris, Subhasree Basu, Thibaut Barnoud, Yongkang Zhao, Peter Somboonsong, Qing Chen, Maureen Murphy. Investigating the impact of astrocytes on targeted therapy of melanoma brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4847.

Impact of Astrocytes on the Injury Induced by In Vitro Ischemia.

Cell cultures are characterized by their simplicity, controllability, and ability to provide detailed basic information on how a particular cell population responds to specific stimuli or insult. These characteristics led to their extensive application in the study of molecular interactions and represent a valuable tool in the study of different pathologies. However, due to the lack of interactions between the different components that form an in vivo system, the results obtained in pure cell cultures not always translate what occurs in vivo. In this context, the use of co-cultures has the advantage of allowing the study of interactions between different types of cells present in a tissue, which in many situations are determinant for the effects obtained. The present study aimed to characterize cortical neuron-glia and neuron-enriched primary cultures and evaluate their response to an ischemic insult. Cell viability was assessed by the MTT assay and cell number/phenotype was analyzed by immunocytochemistry in control cultures and in cells subjected to 4h of oxygen and glucose deprivation. The results obtained demonstrate that astrocytes have a substantial impact on the injury induced by an ischemic insult, thus suggesting that the crosstalk between glia and neurons is crucial to the neuronal protection in conditions of ischemia.

Astrocytes and Its Good Relation with Neurons

The relationship between different cells in the brain starts to be important to neuroscience. Neurons and astrocytes represent the more abundant cells in the human brain and they communicate and speak between them and with other cells, such microglia and oligodendroglia. In the last decade, astroglia has been considered more important than neurons, because they did not many things about them. Astrocytes control neuron connection and synapsis, are involve in processing, transfer and storage brain information, express metabolic genes than increase learning, protect from oxidative stress and inflammation, produce transmitter between neurons and astrocytes, interfere in sleep modulation acting in sleep dynamics and behavior, modulate brain rhythms and help controlling the connections between neurons. Those cells with a lot of functions are playing a central role in our brain and we need to search a lot to understand their functions and contributions to neurodegenerative diseases. Astrocytes are cells development later than neurons in our brain. The physiological role of astrocytes depends on neurons that can drive and indicate the way for the specialized properties of astrocytes [1]. That cells help control the connections between neurons and control the cerebrovasculature in brain [2,3] and the last decade authors discover the role of astrocytes in synaptic physiology, when astrocytes have a bidirectional communication between them and neurons. At this moment, we know than astrocytes regulate synaptic transmission, are involve in the processing, transfer and storage of information and perhaps in memory process in the nervous system [4,5]. The coupling by neuron and astrocytes express key metabolic genes producing adaptations than produce learning [6].A critical dependence exists between astrocytes and neurons because there are a neurotransmitter trafficking and recycling, ion homeostasis, energy metabolism and protection in front of oxidative stress. All indicate us that pathogenic situations produce changes in astrocytes and neurons function and cell viability, such as in Alzheimer’s disease and hepatic encephalopathy in where inflammation can be an important element of destruction of neurons [7]. Astrocytes respond to all forms of central nervous system insults because they have the capacity to change to reactive astrocytes producing reversible alterations in gene expression and cell hypertrophy [8] Protoplasmic or fibrous are the two main subtypes of astrocytes, and they are present in the gray matter and in the white matter respectively [9]. Both astrocytes subtypes make extensive contact with blood vessels. Each astrocytes contact with a few neuronal cell bodies, hundreds of dendrites and tens of thousands of synapses. Moreover, astrocytes can be coupled by gap junctions forming a network between astrocytes themselves and with neurons network. The structural support to the extracellular space and neuromodulation are produced by the impact of astrocytes on synaptic physiology [9]. Furthermore, astrocytes clear extracellular excitatory and inhibitory neurotransmitter, process that help and ensures optim synaptic transmission [10]. In fact D-serine increases the current ?owing through NMDA receptors producing activation and providing a regulatory feedback that controls synaptic transmission and plasticity [11]. In contrast, ATP can bind to purinergic receptors or activates adenosine receptors to modulate neuronal excitability and transformation of information in the synapsis [12]. Furthermore, astrocytes provide modulation of sleep dynamics and behavior [13]. One of the key functions of sleep is its role in memory and astrocytes actively modulate brain rhythms mediating the sleep process to control and produce memory. Computational studies of astrocytes function could help us to understand the two possible sleep functions or theories [14]. Astrocytes have a lot of functions and they are playing a central role in the central nervous system and its disfunction can contribute in many illness in our body [15,16]. We show here the roles of these cells as important cells with a high relationship with neurons.

The Ability of MEAs Containing Cultured Neuroglial Networks to Process Information

The study of the nervous system of human beings is an arduous task. The reasons are that it is very complex and it is internal to the organism. The nervous system is comprised not only of neuronal networks but also of different types of cells that constitute the glial system. Astrocytes, a type of glial cells, have traditionally been considered as passive, supportive cells. However, through the use of neuroscientific techniques, it has recently been demonstrated that astrocytes are actively involved in the processing and regulation of synaptic information, suggesting that brain function arises from the activity of neuron-glia networks. Also in recent studies employing artificial intelligence (AI) techniques, it has been shown that adding artificial astrocytes to Artificial Neural Networks (ANNs), the effectiveness of such networks in classification tasks is markedly improved. At present, the actual impact of astrocytes in neural network function is largely unknown. Therefore, our group is placing increasing emphasis on the study of the influence that astrocytes may have on brain information processing using a rather different perspective based on the use of multielectrode arrays (MEAs). This represents a hybrid approach given that it combines a biological component (cultured cells), hardware technology (MEAs), and AI (computer simulations based on AI techniques to control the system). With this in mind, the objective of this paper is to present a review of the state of the art in the use of MEAs containing nerve cells. This review is intended as a preliminary theoretical analysis on the suitability of these devices to achieve the aforementioned future goal of fusing bioinformatics, micro/nano-technologies, and AI techniques to study these complex systems.

Brain endothelial cells and the glio-vascular complex

We present and discuss the role of endothelial and astroglial cells in managing the blood-brain barrier (BBB) and aspects of pathological alterations in the BBB. The impact of astrocytes, pericytes, and perivascular cells on the induction and maintenance of the gliovascular unit is largely unidentified so far. An understanding of the signaling pathways that lie between these cell types and the endothelium and that possibly are mediated by components of the basal lamina is just beginning to emerge. The metabolism for the maintenance of the endothelial barrier is intimately linked to and dependent on the microenvironment of the brain parenchyma. We report the structure and function of the endothelial cells of brain capillaries by describing structures involved in the regulation of permeability, including transporter systems, caveolae, and tight junctions. There is increasing evidence that caveolae are not only vehicles for endo- and transcytosis, but also important regulators of tight-junction-based permeability. Tight junctions separate the luminal from the abluminal membrane domains of the endothelial cell ("fence function") and control the paracellular pathway ("gate function") thus representing the most significant structure of the BBB. In addition, the extracellular matrix between astrocytes/pericytes and endothelial cells contains numerous molecules with inherent signaling properties that have to be considered if we are to improve our knowledge of the complex and closely regulated BBB.