Issue 1 | March 2016
The common denominator of neurodegenerative diseases, which mainly affect humans, is the progressive death of neural cells resulting in neurological and cognitive deficits. Astroglial cells are central elements of the homoeostasis, defence and regeneration of the central nervous system, and their malfunction or reactivity contribute to the pathophysiology of neurodegenerative diseases. Pathological remodelling of astroglia in neurodegenerative context is multifaceted. Both astroglial atrophy with a loss of function and astroglial reactivity have been identified in virtually all forms of neurodegenerative disorders. Astroglia may represent a novel target for therapeutic strategies aimed at preventing and possibly curing neurodegenerative diseases.
|Pathobiology of Neurodegeneration The Role for Astroglia.pdf||584.08 KB|
A conspicuous ability of the mammalian brain to integrate and process huge amount of spatial, visual and temporal stimuli is a result of its enormous structural complexity functioning in an integrated way as a whole. Here we review recent achievements in the understanding of brain structure and function. A traditional view on the brain as a network of neurons has been extended to the more complicated structure including overlapping and interacting networks of neurons and glial cells. We discuss artificial versus natural neural networks and consider a concept of attractor networks. Moreover, we speculate that each neuron can have an intracellular network on a genetic level, based and functioning on the principle of artificial intelligence. Hence, we speculate that mammalian brain is, in fact, a network of networks. We review different aspects of this structure and propose that the study of brain can be successful only if we utilize the concepts recently developed in nonlinear dynamics: the concept of integrated information, emergence of collective dynamics and taking account of unexpected behavior and regimes due to nonlinearity. Additionally, we discuss perspectives of medical applications to be developed following this research direction.
Most of the human brain mass is occupied by the neocortex, which consists of neurons and non-neurons. The latter cells include astrocytes, a heterogeneous glial cell type. While astrocytes have been considered as neuronsubservient entities for almost a century, it is now becoming evident that they are essential in providing homeostatic support to neural networks and that they also actively participate in information processing in the brain. Astrocytes get excited when neurotransmitters bind to their membrane receptors and feed-back by releasing their own signals. This involves vesicles, which store chemicals termed gliotransmitters or more generally gliosignaling molecules. In the former case chemical messengers get released from astrocytic sites proximal to the synapse, which defines communication to occur in the micro-space of contact between the synapse and the astrocyte. In contrast gliosignaling molecules may also be released into the extracellular space. This mode of release resembles the endocrine system. Hence astrocytes are considered to be part of the gliocrine system in the brain, where the glymphatic system mediates the convection of released molecules. This complex system not only plays a role in cell-to-cell communication but also synchronizes the provision of energy for neural networks. Astrocytes contain glycogen, a form of energy store. Excitation of astrocytes by volume transmitters, such as noradrenaline , released by locus coeruleus neurons, activates adrenergic receptors and stimulates glycogenolysis, providing lactate. This chapter briefly reviews how noradrenaline and astrocytes operate to synchronize excitation and energy provision. Moreover, Ca2+ -dependent fusion of the vesicle membrane with the plasma membrane in astrocytes is discussed.
|Excitation-Energy Coupling and Vesicle-Based Signaling in Astrocytes.pdf||1.74 MB|
Classically, the central nervous system (CNS) was considered to contain neurons and three main types of glial cells - astrocytes, oligodendrocytes, and microglia. Now, it has been clearly established that NG2-glia are a fourth glial cell type that are defined by their expression of the NG2 chondroitin sulfate proteoglycan (Cspg4). NG2-glia are also known as oligodendrocyte precursor cells (OPCs) and express the alpha receptor for platelet-derived growth factor (Pdgfra) as well as other oligodendrocyte lineage markers. NG2-glia are most numerous during CNS development when they are responsible for massive generation of oligodendrocytes, the myelin-forming cells of the CNS. A significant population of NG2-glia persist in the adult CNS, where they generate oligodendrocytes throughout life. A unique feature of NG2-glia is that they receive synaptic inputs from neurons and are able to respond rapidly to neurotransmission via their specific ion channel and receptor profiles. Moreover, synaptic and neuronal integrity depend on NG2-glia. Notably, concomitant disruption of NG2-glia, myelin and neurotransmission are key features of many neuropathologies, including Multiple Sclerosis and Alzheimer’s disease (AD). The fact that neurotransmission both regulates and is reliant on NG2-glia and myelin raises the ‘chicken and egg’ question of what comes first – disruption of NG2-glia/myelin or synapses/neurons. It is more useful to think of neurons, NG2-glia and oligodendrocytes/myelin as being functionally integrated and interdependent units, whereby disruption of any one can result in a vicious cycle with potentially devastating effects on CNS function.
Astrocytes are now recognised as important contributors to synaptic transmission control. Dopamine is a key neuromodulator in the mammalian brain and establishing the potential extent of its actions involving astrocytes is vital to our overall understanding of brain function. Astrocyte membranes can express receptors for dopamine, as well as dopamine transporters, but the full effects of dopamine on astrocytic physiology are still uncertain and its mode of action controversial. Here we overview the developing field of astrocyte-dopamine interaction, focusing on how dopamine affects the pre-eminent astrocytic intracellular signalling messenger – Ca2+ – and the available evidence for astrocyte-mediated effects of dopamine on neurons. We then discuss some of the methodological issues that need to be addressed to help move the field forward.
The effect of 2-aminoethyl diphenylborinate (2-APB), a commonly used drug to modulate inositol-1,4,5-triphosphate (IP3) receptors and transient receptor potential (TRP) channels, on GABAA receptor-mediated currents was studied in neurons from the medial preoptic nucleus (MPN) of rat. 2-APB gradually and reversibly reduced the currents evoked by GABA but had no effect on the currents evoked by glycine. The blocking effect was not mediated by alterations in intracellular calcium concentration and showed a concentration dependence with half maximal effect at ~50 µM 2-APB, for currents evoked by 100 µM, as well as by 1.0 mM GABA, suggesting that 2-APB is not competing with GABA for its binding site at the GABAA receptor. Thus, the present study describes a novel pharmacological property of 2-APB as a non-competitive blocker of GABAA receptors and calls for caution in the interpretation of the results where 2-APB is used to affect IP3 receptors or TRP channels.
Malignant gliomas are primary brain tumors considered to be one of the deadliest cancers. Despite surgical intervention followed by aggressive radio- and chemo-therapies, average survival is approximately 15 months of diagnosis. Recurrent tumors resembling all the characteristics of the original tumor mass and growing in close vicinity to the original site are frequent due to presence of a self-renewing population of cells, glioma stem cells. The cells are resistant to therapies and able to invade the surrounding healthy brain tissue. Indeed, infiltrative growth assisted by numerous interactions with microenvironment are hallmarks of glioma growth. Many research efforts are put forward to understand the mechanisms of invasion. Glioma cells adopted numerous biological strategies to their own advantage to viciously propagate and navigate narrow spaces within the brain. Despite enormous amount of data on malignant gliomas generated by –omics approach which broaden our knowledge on glioma physiology in the last decade, parallel success in discovering new therapies did not happen. Thus, new therapeutic approaches may employ healthy cells of the microenvironment to tame malignant growth are necessary. Here, we highlight current knowledge on glioma origin, infiltrative growth, interactions with the microenvironment and potentials for new therapies.
Stem cells research has passed a long and exciting way from the discovery to clinical applications. Every year more-and-more scientific reports and solid research breakthroughs are published in this fascinating field making it difficult to follow after new discoveries and cover the history. In the current review we overviewed history of stem cells research starting from the discovery and ending with the current state-of-art. We discussed obstacles and future perspectives of the cell-based therapy, with a special focus made on protection and regeneration of the lost functions after injury/degeneration of adult central nervous system.
|CNS Regenerative Medicine and Stem Cells.pdf||482.95 KB|
Alzheimer’s disease (AD) is the most common cause of dementia with an increasing impact on the aging society. Although generations of researchers tried to unravel the pathomechanisms behind this disease, the molecular and cellular mechanisms leading to its onset and progression are still far from being completely understood. Accordingly, only a symptomatic treatment is available until now, and a curative treatment seems to be far-off. On the other hand, several novel therapeutic strategies have been proposed and debated during the last decade. Because of the extensive serotonergic denervation that has been observed in the AD brain and the important role played by serotonin in both, cognition and behavioural control, this neurotransmitter system has become a focus of a concerted research effort to identify new treatments for AD. Therefore, modulation of defined serotonin receptors by specific ligands represents a promising tool for treatments for neurodegenerative diseases like AD. Here we provide an overview of the involvement of the serotonergic system in AD and discuss the underlying molecular mechanisms.