Involvement Of Non-neuronal Cells Research Articles

Brain iron enrichment attenuates α-synuclein spreading after injection of preformed fibrils.

Regional iron accumulation and α-synuclein (α-syn) spreading pathology within the central nervous system are common pathological findings in Parkinson's disease (PD). Whereas iron is known to bind to α-syn, facilitating its aggregation and regulating α-syn expression, it remains unclear if and how iron also modulates α-syn spreading. To elucidate the influence of iron on the propagation of α-syn pathology, we investigated α-syn spreading after stereotactic injection of α-syn preformed fibrils (PFFs) into the striatum of mouse brains after neonatal brain iron enrichment. C57Bl/6J mouse pups received oral gavage with 60, 120, or 240mg/kg carbonyl iron or vehicle between postnatal days 10 and 17. At 12weeks of age, intrastriatal injections of 5-µg PFFs were performed to induce seeding of α-syn aggregates. At 90days post-injection, PFFs-injected mice displayed long-term memory deficits, without affection of motor behavior. Interestingly, quantification of α-syn phosphorylated at S129 showed reduced α-syn pathology and attenuated spreading to connectome-specific brain regions after brain iron enrichment. Furthermore, PFFs injection caused intrastriatal microglia accumulation, which was alleviated by iron in a dose-dependent way. In primary cortical neurons in a microfluidic chamber model in vitro, iron application did not alter trans-synaptic α-syn propagation, possibly indicating an involvement of non-neuronal cells in this process. Our study suggests that α-syn PFFs may induce cognitive deficits in mice independent of iron. However, a redistribution of α-syn aggregate pathology and reduction of striatal microglia accumulation in the mouse brain may be mediated via iron-induced alterations of the brain connectome.

Pathological Mechanisms of Bortezomib-Induced Peripheral Neuropathy

Bortezomib, a first-generation proteasome inhibitor widely used in chemotherapy for hematologic malignancy, has effective anti-cancer activity but often causes severe peripheral neuropathy. Although bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, there are no recommended therapeutics for its prevention or treatment. One of the most critical problems is a lack of knowledge about pathological mechanisms of BIPN. Here, we summarize the known mechanisms of BIPN based on preclinical evidence, including morphological abnormalities, involvement of non-neuronal cells, oxidative stress, and alterations of transcriptional programs in both the peripheral and central nervous systems. Moreover, we describe the necessity of advancing studies that identify the potential efficacy of approved drugs on the basis of pathological mechanisms, as this is a convincing strategy for rapid translation to patients with cancer and BIPN.

Neuron-Astrocyte Interactions in Parkinson's Disease.

Parkinson’s disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and postural instability due to a loss of nigrostriatal dopaminergic neurons. Although the pathogenesis in sporadic PD remains unknown, there is a consensus on the involvement of non-neuronal cells in the progression of PD pathology. Astrocytes are the most numerous glial cells in the central nervous system. Normally, astrocytes protect neurons by releasing neurotrophic factors, producing antioxidants, and disposing of neuronal waste products. However, in pathological situations, astrocytes are known to produce inflammatory cytokines. In addition, various studies have reported that astrocyte dysfunction also leads to neurodegeneration in PD. In this article, we summarize the interaction of astrocytes and dopaminergic neurons, review the pathogenic role of astrocytes in PD, and discuss therapeutic strategies for the prevention of dopaminergic neurodegeneration. This review highlights neuron-astrocyte interaction as a target for the development of disease-modifying drugs for PD in the future.

MCP1-CCR2 and neuroinflammation in the ALS motor cortex with TDP-43 pathology

BackgroundThe involvement of non-neuronal cells and the cells of innate immunity has been attributed to the initiation and progression of ALS. TDP-43 pathology is observed in a broad spectrum of ALS cases and is one of the most commonly shared pathologies. The potential involvement of the neuroimmune axis in the motor cortex of ALS patients with TDP-43 pathology needs to be revealed. This information is vital for building effective treatment strategies.MethodsWe investigated the presence of astrogliosis and microgliosis in the motor cortex of ALS patients with TDP-43 pathology. prpTDP-43A315T-UeGFP mice, corticospinal motor neuron (CSMN) reporter line with TDP-43 pathology, are utilized to reveal the timing and extent of neuroimmune interactions and the involvement of non-neuronal cells to neurodegeneration. Electron microscopy and immunolabeling techniques are used to mark and monitor cells of interest.ResultsWe detected both activated astrocytes and microglia, especially rod-like microglia, in the motor cortex of patients and TDP-43 mouse model. Besides, CCR2+ TMEM119- infiltrating monocytes were detected as they penetrate the brain parenchyma. Interestingly, Betz cells, which normally do not express MCP1, were marked with high levels of MCP1 expression when diseased.ConclusionsThere is an early contribution of a neuroinflammatory response for upper motor neuron (UMN) degeneration with respect to TDP-43 pathology, and MCP1-CCR2 signaling is important for the recognition of diseased upper motor neurons by infiltrating monocytes. The findings are conserved among species and are observed in both ALS and ALS-FTLD patients.

Non-Neuronal Cells in the Hypothalamic Adaptation to Metabolic Signals.

Although the brain is composed of numerous cell types, neurons have received the vast majority of attention in the attempt to understand how this organ functions. Neurons are indeed fundamental but, in order for them to function correctly, they rely on the surrounding “non-neuronal” cells. These different cell types, which include glia, epithelial cells, pericytes, and endothelia, supply essential substances to neurons, in addition to protecting them from dangerous substances and situations. Moreover, it is now clear that non-neuronal cells can also actively participate in determining neuronal signaling outcomes. Due to the increasing problem of obesity in industrialized countries, investigation of the central control of energy balance has greatly increased in attempts to identify new therapeutic targets. This has led to interesting advances in our understanding of how appetite and systemic metabolism are modulated by non-neuronal cells. For example, not only are nutrients and hormones transported into the brain by non-neuronal cells, but these cells can also metabolize these metabolic factors, thus modifying the signals reaching the neurons. The hypothalamus is the main integrating center of incoming metabolic and hormonal signals and interprets this information in order to control appetite and systemic metabolism. Hence, the factors transported and released from surrounding non-neuronal cells will undoubtedly influence metabolic homeostasis. This review focuses on what is known to date regarding the involvement of different cell types in the transport and metabolism of nutrients and hormones in the hypothalamus. The possible involvement of non-neuronal cells, in particular glial cells, in physiopathological outcomes of poor dietary habits and excess weight gain are also discussed.

Bovine herpesvirus-5 infection in a rabbit experimental model: Immunohistochemical study of the cellular response in the CNS

Since little information is available regarding cellular antigen mapping and the involvement of non-neuronal cells in the pathogenesis of bovine herpesvirus type 5 (BHV-5) infection, it were determined the BHV-5 distribution, the astrocytic reactivity, the involvement of lymphocytes and the presence of matrix metalloproteinase (MMP)-9 in the brain of rabbits experimentally infected with BHV-5. Twelve New Zealand rabbits that were seronegative for BHV-5 were used for virus inoculation, and five rabbits were used as mock-infected controls. The rabbits were kept in separate areas and were inoculated intranasally with 500 μl of virus suspension (EVI 88 Brazilian isolate) into each nostril (virus titer, 107.5 TCID50). Control rabbits were inoculated with the same volume of minimum essential medium. Five days before virus inoculation, the rabbits were submitted to daily administration of dexamethasone. After virus inoculation, the rabbits were monitored clinically on a daily basis. Seven rabbits showed respiratory symptoms and four animals exhibited neurological symptoms. Tissue sections were collected for histological examination and immunohistochemistry to examine BHV-5 antigens, astrocytes, T and B lymphocytes and MMP-9. By means of immunohistochemical and PCR methods, BHV-5 was detected in the entire brain of the animals which presented with neurological symptoms, especially in the trigeminal ganglion and cerebral cortices. Furthermore, BHV-5 antigens were detected in neurons and/or other non-neural cells. In addition to the neurons, most infiltrating CD3 T lymphocytes observed in these areas were positive for MMP-9 and also for BHV-5 antigen. These infected cells might contribute to the spread of the virus to the rabbit brain along the trigeminal ganglia and olfactory nerve pathways.

Non-neuronal cells, inflammation and epilepsy (Commentary on Aronicaet al.)

Extending the classical neurocentric view that epileptogenesis is driven by neuronal alterations, accumulating experimental and clinical evidence points to the possible involvement of non-neuronal cells, such as glia, endothelial cells, and leukocytes in the pathophysiology of epilepsy, specifically by means of inflammatory mechanisms. Inflammatory responses, notably interleukin (IL)-1b signaling, have been shown to be associated with status epilepticus and seizure frequency (Marchi et al., 2009). As shown in experimental models and in tissue from patients with epilepsy, seizures evoke the release of cytokines not just from neurons but also from glial cells and endothelial cells (Ravizza et al., 2008). Furthermore, the contribution of non-neuronal cells to the induction of neuronal death following pilocarpine-induced status epilepticus has been demonstrated (Rogawsi, 2005; Ding et al., 2007). Several key events that lead to inflammatory responses following seizures have been identified. Seizures can induce blood–brain barrier disruption (Janigro, 2007) and ⁄ or angiogenesis characterized by poor barrier function (Rigau et al., 2007), thereby permitting serum albumin entry into the brain (van Vliet et al., 2007), followed by astrocytic albumin uptake (Ivens et al., 2007); and activation of endothelial and leukocytes interactions (Fabene et al., 2008; Kleen & Holmes, 2008; Ransohoff, 2009). However, despite this wealth of data, the mechanisms underlying enduring immune and inflammatory responses in temporal lobe epilepsy (TLE) remain largely elusive. As described in the current issue of EJN, Aronica et al. (2010) took an important step toward resolving this issue. They demonstrated the selective up-regulation of a proinflammatory signalling-associated microRNA (miRNA) in a rat model of TLE as well as in human TLE. MicroRNAs are genomically encoded small non-coding RNAs that influence the translation and stability of mRNAs (Zhao & Srivastava, 2007). Aronica et al. (2010) focused on miR-146a, a microRNA that is induced by pro-inflammatory stimuli, modulating innate immunity through regulation of Toll-like receptor signaling and cytokine responses (Taganov et al., 2006). miR-146a is also known to play a functional role in T lymphocyte-mediated immune responses (Curtale et al., 2010). In order to understand the regulation and function of miR-146a in epilepsy, Aronica et al. (2010) investigated the dynamics of miR-146a expression during epileptogenesis in a rat model of TLE. Furthermore, they studied the expression and cellular distribution of this microRNA in hippocampal tissue obtained from TLE patients with hippocampal sclerosis. The authors report an increase of miR-146a expression in the CA3 region of rats during latent and chronic phases of experimental epilepsy, as well as in the human tissue. It is important to note that miR-146a expression was evident not only in neurons, but most prominently in GFAP-positive reactive astrocytes, underscoring their key role for orchestrating inflammatory responses in epilepsy. The results of this study suggest new avenues toward the identification of cellular mechanisms underlying epileptogenesis and persistent functional alterations in chronic epilepsy. Furthermore, these results indicate that miRNAs, linking astrocytes with inflammatory mechanisms, are potentially promising new cellular targets for the development of antiepileptic drugs.

A review of central neuropathic pain states

Central neuropathic pain is an important and disabling but often neglected problem following central nervous system lesions. The present review highlights recent advances in the understanding of the underlying mechanisms and in the diagnosis and treatment of central pain. Within the past year, the field of central pain has moved toward a more integrative understanding of central pain. The involvement of nonneuronal cells and interaction between multiple areas of the central nervous system has been recognized as important in the underlying mechanisms. The interest for conditions other than spinal cord injury, multiple sclerosis, and stroke has increased, and continued discussions on clear clinical diagnostic criteria are needed. The treatment of central pain is still a great challenge, but recent evidence points to tricyclic antidepressants, gabapentin and pregabalin, and selective serotonin-noradrenaline reuptake inhibitors as first-line drugs in central pain. An increased understanding of the psychosocial aspects of central pain also has implications for the treatment. Increased insight into the mechanisms of central pain will hopefully lead to increased efforts to study mechanism-based treatment of central pain.

The Release of Substance P From Cultured Dorsal Root Ganglion Neurons Requires the Non-neuronal Cells Around These Neurons

Substance P is known to be released from dorsal root ganglion (DRG) neurons, but the possible involvement of non-neuronal cells in the process of substance P release is not known. During the culture period, the number of surviving DRG neurons, the total substance P content from the culture medium and DRG cells, and the total protein of DRG cells were monitored. Both the number of surviving neurons and the total substance P content decreased in a time-dependent manner, whereas the total protein synthesis was increased. The localization of substance P in small-to-medium–sized neurons was further confirmed by immunocytochemistry. Finally, the substance P release levels from the neuronal and non-neuronal enrichments were investigated by radioimmunoassay. Both partially purified DRG neurons and non-neuronal cells exhibited a weaker substance P release response to capsaicin or KCl, relative to unpurified DRG cells. The total substance P content from the partially purified DRG neurons was almost the same as that from the unpurified DRG cells, but much more than that from the partially purified DRG non-neuronal cells. These findings suggest that substance P is released from DRG neurons, and this process should require the coexistence of neurons and non-neuronal cells.

Involvement of non-neuronal cells in entorhinal-hippocampal reorganization following lesions.

Entorhinal lesion leads to anterograde degeneration of perforant path fibers in their main hippocampal termination zones. Subsequently, remaining fibers sprout and form new synapses on the denervated dendrites. This degeneration and reorganization is accompanied by sequential changes in glial morphology and function. Within a few hours following the lesion, amoeboid microglia migrate into the zone of denervation. Some hours later, signs of activation can be seen on astrocytes in the zone of denervation, where both cell types proliferate and remain in an activated state for more than two weeks. These activated glial cells might be involved in lesion-induced plasticity in at least two ways: (1) by releasing cytokines and growth factors which regulate layer-specific sprouting and (2) by phagocytosis of axonal debris, because myelin sheaths act as obstacles for sprouting fibers in the central nervous system. Whereas direct evidence for the former is still missing, the latter was investigated using phagocytosis-dependent labeling techniques. Both microglial cells and astrocytes incorporate axonal debris. Phagocytosing microglial cells develop the immune phenotype of antigen-presenting cells, whereas astrocytes strongly express FasL (CD95L), which induces apoptosis of activated lymphocytes. Thus, the interaction of glial cells with immune cells might be another, previously underestimated, aspect of reorganization following entorhinal lesion.

P-435 - Possible involvement of non-neuronal cells in promotion of neuronal survival by basic fibroblast growth factor and epidermal growth factor in cultured brain neurons.

P-435 - Possible involvement of non-neuronal cells in promotion of neuronal survival by basic fibroblast growth factor and epidermal growth factor in cultured brain neurons.