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Characterization of region-specific astrocytes. a GFAP expression in cortical and striatal astrocytes was assessed by immunocytochemistry and normalized to the number of cells. Values represent the mean ± SEM of n = 3 independent experiments of GFAP fluorescence/cell determined by ImageJ software. Differences between two groups were analyzed by Student’s t test (**p < 0.01 vs. striatal astrocytes). b Representative merged images showing in green GFAP-positive cortical (left) and striatal (right) astrocytes and in blue their nuclei stained with DAPI. c ALDH1L1 expression in cortical and striatal astrocytes was assessed by immunocytochemistry and normalized to the number of cells. Values represent the mean ± SEM of n = 3 independent experiments of ALDH1L1 fluorescence/cell determined by ImageJ software. Differences between two groups were analyzed by Student’s t test. d Representative merged images showing in green cortical (left) and striatal (right) astrocytes positive for ALDH1L1 and in blue their nuclei stained with DAPI
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Evidence shows significant heterogeneity in astrocyte gene expression and function. We previously demonstrated that brain-derived neurotrophic factor (BDNF) exerts protective effects on whole brain primary cultured rat astrocytes treated with 3-nitropropionic acid (3NP), a mitochondrial toxin widely used as an in vitro model of Hunting...
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The growth factor brain-derived neurotrophic factor (BDNF), and its receptor tropomyosin-related kinase receptor type B (TrkB) play an active role in numerous areas of the adult brain, where they regulate the neuronal activity, function, and survival. Upregulation and downregulation of BDNF expression are critical for the physiology of neuronal cir...
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... The alterations in ferroportin and ACSL4 in the striatum were not observed in the hippocampus and cortex. The striatum is known to have higher iron and microglial content than the cortex and hippocampus (Ramos et al., 2014;Ward et al., 2014;Grabert et al., 2016;Keller et al., 2018;Saba et al., 2020), which may explain the differential regional response. Further, GFAP-immunoreactivity was unaltered in the striatum but was increased in both the hippocampus and the cortex. ...
... This is unsurprising as astrocytes from the mouse striatum and hippocampus display diversity as confirmed by transcriptomic, proteomic, morphological, and functional evidence (Chai et al., 2017). Further, cortical astrocytes have been shown to release greater amounts of TNFα in response to LPS stimulation than striatal astrocytes (Saba et al., 2020), consistent with our findings of increased astroglial immunoreactivity in the cortex but not in the striatum. Regional molecular comparisons were not possible with the substantia nigra as only metal and histological analyses were performed. ...
Iron dyshomeostasis and neuroinflammation, characteristic features of the aged brain, and exacerbated in neurodegenerative disease, may induce oxidative stress-mediated neurodegeneration. In this study, the effects of potential priming with mild systemic iron injections on subsequent lipopolysaccharide (LPS)-induced inflammation in adult C57Bl/6J mice were examined. After cognitive testing, regional brain tissues were dissected for iron (metal) measurements by total reflection X-ray fluorescence and synchrotron radiation X-Ray fluorescence-based elemental mapping; and iron regulatory, ferroptosis-related, and glia-specific protein analysis, and lipid peroxidation by western blotting. Microglial morphology and astrogliosis were assessed by immunohistochemistry. Iron only treatment enhanced cognitive performance on the novel object location task compared with iron priming and subsequent LPS-induced inflammation. LPS-induced inflammation, with or without iron treatment, attenuated hippocampal heme oxygenase-1 and augmented 4-hydroxynonenal levels. Conversely, in the cortex, elevated ferritin light chain and xCT (light chain of System X c ⁻ ) were observed in response to LPS-induced inflammation, without and with iron-priming. Increased microglial branch/process lengths and astrocyte immunoreactivity were also increased by combined iron and LPS in both the hippocampus and cortex. Here, we demonstrate iron priming and subsequent LPS-induced inflammation led to iron dyshomeostasis, compromised antioxidant function, increased lipid peroxidation and altered neuroinflammatory state in a brain region-dependent manner.
... Europinidin might influence neurotransmitter levels by inhibiting AChE activity, increasing GABA levels, and promoting DA synthesis or release. These actions could help restore neurotransmitter balance, which is often disrupted in HD [45][46][47][48][49][50]. ...
Huntington’s disease (HD) is a neurodegenerative disease that causes progressive motor and cognitive dysfunction. There is no cure for HD, and current therapeutics can only manage the signs and symptoms as well as slowing disease progression. This investigation examines the possible therapeutic advantages of europinidin in 3-nitropropionic acid (3-NPA) injected HD in rats. Wistar rats were randomly assigned to five groups (n = 6): normal control, 3-NPA (10 mg/kg, i.p.), 3-NPA + europinidin-10 (10 mg/kg, p.o.), 3-NPA + europinidin-20 (20 mg/kg, p.o.), and europinidin alone (20 mg/kg, p.o.) for 15-day. Various behavioral and biochemical parameters including antioxidant levels, oxidative stress, pro-inflammatory markers, mitochondrial enzyme complex, and neurotransmitters were assessed. Europinidin restored biochemical, mitochondrial dysfunction, oxidative stress, neurotransmitter, and pro-inflammatory parameters disrupted by 3-NPA. Here we show that europinidin attenuates 3-NPA-induced neurodegeneration in rat models of HD. Europinidin modulates oxidative stress, enhances antioxidants, restores mitochondrial enzyme complex activity, reduces neuroinflammation, and modulates neurotransmitter levels. Our findings reveal the potential of europinidin as a novel therapeutic agent for the treatment of HD. This study also provides new insights into the molecular mechanisms of europinidin-mediated neuroprotection and may have a beneficial role in the management of neurological diseases.
... Astrocytes have been implicated in the development of and in the protection from these diseases [16][17][18]. Although they have traditionally been viewed as simple, homogenous cells providing support to neurons, we now recognize that astrocytes from different brain regions are heterogeneous [19]. Chai et al. demonstrated that cortical astrocytes and hippocampal astrocytes were similar when comparing RNA sequencing data, but hippocampal and striatal astrocytes were shown to be different populations [20]. ...
Astrocytes are crucial in the regulation of neurotransmitter homeostasis, and while their involvement in the dopamine (DA) tripartite synapse is acknowledged, it necessitates a more comprehensive investigation. In the present study, experiments were conducted on primary astrocyte cultures from the striatum and cortex of neonatal rats. The pharmacological intricacies of DA uptake, including dependence on time, temperature, and concentration, were investigated using radiolabelled [3H]-DA. The mRNA expression of transporters DAT, NET, PMAT, and OCTs was evaluated by qPCR. Notably, astrocytes from both brain regions exhibited prominent mRNA expression of NET and PMAT, with comparatively lower expression of DAT and OCTs. The inhibition of DA uptake by the DAT inhibitor, GBR12909, and NET inhibitors, desipramine and nortriptyline, impeded DA uptake in striatal astrocytes more than in cortical astrocytes. The mRNA expression of NET and PMAT was significantly upregulated in cortical astrocytes in response to the DA receptor agonist apomorphine, while only the mRNA expression of NET exhibited changes in striatal astrocytes. Haloperidol, a DA receptor antagonist, and L-DOPA, a DA precursor, did not induce significant alterations in transporter mRNA expression. These findings underscore the intricate and region-specific mechanisms governing DA uptake in astrocytes, emphasizing the need for continued exploration to unravel the nuanced dynamics of astrocytic involvement in the DA tripartite synapse.
... Rapid methodological developments resulted in the identification of transcriptional astrocytic expression profiles in physiological as well as pathological states [15][16][17]. These assignments led to the translation from structural phenotyping to region-and context-specific functions thereby identifying astrocytic subpopulations with a spectrum of potential effector functions ranging from neurotoxic properties with impaired autophagy, synapse elimination, and dopamine regulation [18,19] to neuroprotective signatures promoting CNS recovery and repair by secreting transforming growth factor β (TGF-β) and brain derived neurotrophic factor (BDNF), angiopoietin-1 (ANG1), and expression of connexin-43 (CX43) [20][21][22]. ...
... In this study, the authors provide evidence of elevated CSF levels of IL-1β, IL-1ra, IL-13, IL-17, MIP-1α, and G-CSF using a cytokine proteomic assay matching the findings of the present transcriptomic findings. Additionally, regiondependent responses have been described in mouse models of Huntington's disease [20,66]. Striatal mouse astrocytes have been shown to respond context-specifically by G i -GPCR signaling in vivo with an upregulation Fig. 7 In-situ hybridization of oligodendrocyte-associated transcripts in the cortex of MBP29-hα-syn mice. ...
The growing recognition of a dichotomous role of astrocytes in neurodegenerative processes has heightened the need for unraveling distinct astrocytic subtypes in neurological disorders. In multiple system atrophy (MSA), a rare, rapidly progressing atypical Parkinsonian disease characterized by increased astrocyte reactivity. However the specific contribution of astrocyte subtypes to neuropathology remains elusive. Hence, we first set out to profile glial fibrillary acidic protein levels in astrocytes across the human post mortem motor cortex, putamen, and substantia nigra of MSA patients and observed an overall profound astrocytic response. Matching the post mortem human findings, a similar astrocytic phenotype was present in a transgenic MSA mouse model. Notably, MSA mice exhibited a decreased expression of the glutamate transporter 1 and glutamate aspartate transporter in the basal ganglia, but not the motor cortex. We developed an optimized astrocyte isolation protocol based on magnetic-activated cell sorting via ATPase Na+/K+ transporting subunit beta 2 and profiled the transcriptomic landscape of striatal and cortical astrocytes in transgenic MSA mice. The gene expression profile of astrocytes in the motor cortex displayed an anti-inflammatory signature with increased oligodendroglial and pro-myelinogenic expression pattern. In contrast, striatal astrocytes were defined by elevated pro-inflammatory transcripts accompanied by dysregulated genes involved in homeostatic functions for lipid and calcium metabolism. These findings provide new insights into a region-dependent, dichotomous astrocytic response—potentially beneficial in the cortex and harmful in the striatum—in MSA suggesting a differential role of astrocytes in MSA-related neurodegenerative processes.
... In ALS patient-specific VCP (valosin-containing protein)-mutant MNs, a significant increase in cytoplasmic TDP-43 (TAR DNA-binding protein 43) levels and ER (endoplasmic reticulum) stress was observed as primary pathogenic events followed by secondary events involving impaired mitochondria [51]. One study reported that 3-nitropropionic acid (a mitochondrial toxin) treatment induces the secretion of soluble neuroprotective factors in response to BDNF in striatal astrocytes expressing mutant huntingtin [52]. Under normal physiological conditions, astrocytes undergo internalization and clear neuronal mitochondria in a specialized manner called trans mitophagy. ...
Neurodegeneration is an age-dependent progressive phenomenon with no defined cause. Aging is the main risk factor for neurodegenerative diseases. During aging, activated microglia undergo phenotypic alterations that can lead to neuroinflammation, which is a well-accepted event in the pathogenesis of neurodegenerative diseases. Several common mechanisms are shared by genetically or pathologically distinct neurodegenerative diseases, such as excitotoxicity, mitochondrial deficits and oxidative stress, protein misfolding and translational dysfunction, autophagy and microglia activation. Progressive loss of the neuronal population due to increased oxidative stress leads to neurodegenerative diseases, mostly due to the accumulation of dysfunctional mitochondria. Mitochondrial dysfunction and excessive neuroinflammatory responses are both sufficient to induce pathology in age-dependent neurodegeneration. Therefore, mitochondrial quality control is a key determinant for the health and survival of neuronal cells in the brain. Research has been primarily focused to demonstrate the significance of neuronal mitochondrial health, despite the important contributions of non-neuronal cells that constitute a significant portion of the brain volume. Moreover, mitochondrial morphology and function are distinctly diverse in different tissues; however, little is known about their molecular diversity among cell types. Mitochondrial dynamics and quality in different cell types markedly decide the fate of overall brain health; therefore, it is not justifiable to overlook non-neuronal cells and their significant and active contribution in facilitating overall neuronal health. In this review article, we aim to discuss the mitochondrial quality control of different cell types in the brain and how important and remarkable the diversity and highly synchronized connecting property of non-neuronal cells are in keeping the neurons healthy to control neurodegeneration.
... When mHtt was chosen to be expressed in astrocytes, no notable changes appeared in glia or neurons, but mice showed pathological symptoms in the late stage. HD astrocytes present defects in the secretion of chemokines CCL5, BDNF and low levels of K + channels, which can regulate neuronal excitability Saba et al., 2020). In HD, nuclear factor-κB (NF-κB) acts as an inflammatory indicator and regulates the expression of various inflammatory cytokines, including IL-1 and TNF-α (Yusuf et al., 2021). ...
Pain is common and frequent in many neurodegenerative diseases, although it has not received much attention. In Huntington’s disease (HD), pain is often ignored and under-researched because attention is more focused on motor and cognitive decline than psychiatric symptoms. In HD progression, pain symptoms are complex and involved in multiple etiologies, particularly mental issues such as apathy, anxiety and irritability. Because of psychiatric issues, HD patients rarely complain of pain, although their bodies show severe pain symptoms, ultimately resulting in insufficient awareness and lack of research. In HD, few studies have focused on pain and pain-related features. A detailed and systemic pain history is crucial to assess and explore pain pathophysiology in HD. This review provides an overview concentrating on pain-related factors in HD, including neuropathology, frequency, features, affecting factors and mechanisms. More attention and studies are still needed in this interesting field in the future.
... In ALS patient-specific VCP (valosin-containing protein)-mutant MNs, a significant increase in cytoplasmic TDP-43 (TAR DNA-binding protein 43) levels and ER (endoplasmic reticulum) stress was observed as primary pathogenic events as well as secondary mitochondrial dysfunction and oxidative stress [18]. In an in vitro model of HD (Huntington's disease) i.e. 3NP (3-nitropropionic acid, a mitochondrial toxin) treatment induces secretion of soluble neuroprotective factors in response to BDNF (brain-derived neurotrophic factor) in striatal astrocytes that selectively protect neurons expressing mutant huntingtin [19]. Under normal physiological conditions, astrocytes internalize and clears neuronal mitochondria in a specialized process called trans-mitophagy. ...
Neurodegeneration is an age-dependent progressive phenomenon with no defined cause. Aging is the main risk factor for neurodegenerative diseases. During aging, activated microglia undergoes phenotypic alterations that can lead to neuroinflammation, which is well accepted event in the pathogenesis of neurodegenerative diseases. Several common mechanisms are shared by genetically or pathologically distinct neurodegenerative diseases, such as excitotoxicity, mitochondrial deficits and oxidative stress, protein misfolding and translational dysfunction, autophagy and microglia activation. Progressive loss of neuronal population due to increased oxidative stress leads to neurodegenerative diseases mostly due to the accumulation of dysfunctional mitochondria. Mitochondrial dysfunction and excessive neuroinflammatory responses are both sufficient to induce pathology in age-dependent neurodegeneration. Therefore, mitochondrial quality control is key determinant for the health and survival of neuronal cells in the brain. Research has been primarily focused to demonstrate the significance of neuronal mitochondrial health, despite the important contributions of non-neuronal cells that constitutes significant portion of the brain volume. Moreover, mitochondrial morphology and function are distinctly diverse in different tissues; however, little is known about their molecular diversity among cell types. Mitochondrial dynamics and quality in different cell types markedly decides the fate of overall brain health, therefore it is not justifiable to overlook non-neuronal cells and their significant and active contribution in facilitating overall neuronal health. In this review article, we aim to discuss the mitochondrial quality control of different cell types in the brain and how important and remarkable is the diversity and highly synchronized connecting property of non-neuronal cells in keeping the neurons healthy to control neurodegeneration.
... What's more, the mutation of huntingtin gene affects the processing and secretion of the BDNF in astrocytes, leads to progressive degeneration of striatal GABAergic medium spiny neurons and decreases BDNF level in the brain of HD patients (Wang et al., 2012;Bawari et al., 2019). In return, BDNF modulates striatal astrocyte function by inducing astrocyte to secrete soluble neuroprotective factors that selectively protect neurons expressing mutant huntingtin (Saba et al., 2020). ...
Brain derived neurotrophic factor (BDNF) has multiple biological functions which are mediated by the activation of two receptors, tropomyosin receptor kinase B (TrkB) receptor and the p75 neurotrophin receptor, involving in physiological and pathological processes throughout life. The diverse presence and activity of BDNF indicate its potential role in the pathogenesis, progression and treatment of both neurological and psychiatric disorders. This review is to provide a comprehensive assessment of the current knowledge and future directions in BDNF-associated research in the central nervous system (CNS), with an emphasis on the physiological and pathological functions of BDNF as well as its potential treatment effects in CNS diseases, including depression, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and cerebral ischemic stroke.
... In this context, Song et al. 65 demonstrated that the incorporation of 0.1 wt% of GO on PCL/GO nanofibers, increased 1.7-fold the expression of Gfap in neuron-like rat pheochromocytoma cells (PC12 line) while neural stem cells (NSCs) favorably differentiated into astrocytes on rGO microfibers or graphene foams, enhancing the expression of Gfap by 1.43-fold and 2.5-fold, respectively 66,67 . Additionally, the buffering properties of astrocyte glutamate transporters, such as Glast, keep extracellular brain levels of glutamate at low concentrations since its accumulation in the synaptic space produces neuronal overstimulation and excitotoxicity, and has been involved in several neurodegenerative diseases 64,68 . Several works reported Glast localization in the cell membrane and cellular extensions in cultured rat brain astrocytes 36,64,68 . ...
... Additionally, the buffering properties of astrocyte glutamate transporters, such as Glast, keep extracellular brain levels of glutamate at low concentrations since its accumulation in the synaptic space produces neuronal overstimulation and excitotoxicity, and has been involved in several neurodegenerative diseases 64,68 . Several works reported Glast localization in the cell membrane and cellular extensions in cultured rat brain astrocytes 36,64,68 . Interestingly, some authors identified a functional overlap between Gfap and Glast 69,70 . ...
Composites of polymer and graphene-based nanomaterials (GBNs) combine easy processing onto porous 3D membrane geometries due to the polymer and cellular differentiation stimuli due to GBNs fillers. Aiming to step forward to the clinical application of polymer/GBNs composites, this study performs a systematic and detailed comparative analysis of the influence of the properties of four different GBNs: (i) graphene oxide obtained from graphite chemically processes (GO); (ii) reduced graphene oxide (rGO); (iii) multilayered graphene produced by mechanical exfoliation method (G mec ); and (iv) low-oxidized graphene via anodic exfoliation (G anodic ); dispersed in polycaprolactone (PCL) porous membranes to induce astrocytic differentiation. PCL/GBN flat membranes were fabricated by phase inversion technique and broadly characterized in morphology and topography, chemical structure, hydrophilicity, protein adsorption, and electrical properties. Cellular assays with rat C6 glioma cells, as model for cell-specific astrocytes, were performed. Remarkably, low GBN loading (0.67 wt%) caused an important difference in the response of the C6 differentiation among PCL/GBN membranes. PCL/rGO and PCL/GO membranes presented the highest biomolecule markers for astrocyte differentiation. Our results pointed to the chemical structural defects in rGO and GO nanomaterials and the protein adsorption mechanisms as the most plausible cause conferring distinctive properties to PCL/GBN membranes for the promotion of astrocytic differentiation. Overall, our systematic comparative study provides generalizable conclusions and new evidences to discern the role of GBNs features for future research on 3D PCL/graphene composite hollow fiber membranes for in vitro neural models.
... However, whilst the therapeutic efficacy of exogenous BDNF treatment has been well documented following ischaemic damage to the motor cortex [42,43], to the best of our knowledge, the role of BDNF in promoting cognitive recovery following strokes targeting the PFC has yet to be assessed. Indeed, amounting work supports extensive heterogeneity in the cellular, molecular and transcriptional profiles of different cortical regions of the mammalian brain [44][45][46]. Recent work from Saba and colleagues has further demonstrated neuroprotective properties of exogenous BDNF against 3-nitroprionic acid (3-NP)-induced excitotoxic damage in cultures derived from striatal, but not cortical, astrocytes [47]. ...
Stroke-induced cognitive impairments remain of significant concern, with very few treatment options available. The involvement of glycosaminoglycans in neuroregenerative processes is becoming better understood and recent advancements in technology have allowed for cost-effective synthesis of novel glycomimetics. The current study evaluated the therapeutic potential of two novel glycomimetics, compound A and G, when administered systemically five-days post-photothrombotic stroke to the PFC. As glycosaminoglycans are thought to facilitate growth factor function, we also investigated the combination of our glycomimetics with intracerebral, recombinant human brain-derived neurotrophic factor (rhBDNF). C56BL/6J mice received sham or stroke surgery and experimental treatment (day-5), before undergoing the object location recognition task (OLRT). Four-weeks post-surgery, animals received prelimbic injections of the retrograde tracer cholera toxin B (CTB), before tissue was collected for quantification of thalamo-PFC connectivity and reactive astrogliosis. Compound A or G treatment alone modulated a degree of reactive astrogliosis yet did not influence spatial memory performance. Contrastingly, compound G+rhBDNF treatment significantly improved spatial memory, dampened reactive astrogliosis and limited stroke-induced loss of connectivity between the PFC and midline thalamus. As rhBDNF treatment had negligible effects, these findings support compound A acted synergistically to enhance rhBDNF to restrict secondary degeneration and facilitate functional recovery after PFC stroke.
