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Acta Neuropathol Commun ; 10(1): 50, 2022 04 11.
Article En | MEDLINE | ID: mdl-35410438

Traumatic brain injury (TBI) is associated with the development of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy (CTE). Current consensus diagnostic criteria define the pathognomonic cortical lesion of CTE neuropathologic change (CTE-NC) as a patchy deposition of hyperphosphorylated tau in neurons, with or without glial tau in thorn-shaped astrocytes, typically towards the depths of sulci and clustered around small blood vessels. Nevertheless, although incorporated into consensus diagnostic criteria, the contribution of the individual cellular components to identification of CTE-NC has not been formally evaluated. To address this, from the Glasgow TBI Archive, cortical tissue blocks were selected from consecutive brain donations from contact sports athletes in which there was known to be either CTE-NC (n = 12) or Alzheimer's disease neuropathologic change  (n = 4). From these tissue blocks, adjacent tissue sections were stained for tau antibodies selected to reveal either solely neuronal pathology (3R tau; GT-38) or mixed neuronal and astroglial pathologies (4R tau; PHF-1). These stained sections were then randomised and independently assessed by a panel of expert neuropathologists, blind to patient clinical history and primary antibody applied to each section, who were asked to record whether CTE-NC was present. Results demonstrate that, in sections stained for either 4R tau or PHF-1, consensus recognition of CTE-NC was high. In contrast, recognition of CTE-NC in sections stained for 3R tau or GT-38 was poor; in the former no better than chance. Our observations demonstrate that the presence of both neuronal and astroglial tau pathologies facilitates detection of CTE-NC, with its detection less consistent when neuronal tau pathology alone is visible. The combination of both glial and neuronal pathologies, therefore, may be required for detection of CTE-NC.

Alzheimer Disease , Brain Injuries, Traumatic , Chronic Traumatic Encephalopathy , Alzheimer Disease/diagnosis , Alzheimer Disease/pathology , Astrocytes/pathology , Brain/pathology , Brain Injuries, Traumatic/pathology , Chronic Traumatic Encephalopathy/diagnosis , Chronic Traumatic Encephalopathy/pathology , Humans , Neuropathology , tau Proteins/metabolism
Cells ; 11(8)2022 Apr 15.
Article En | MEDLINE | ID: mdl-35456027

Glioblastoma (GBM) are among the most common malignant central nervous system (CNS) cancers, they are relatively rare. This evidence suggests that the CNS microenvironment is naturally equipped to control proliferative cells, although, rarely, failure of this system can lead to cancer development. Moreover, the adult CNS is innately non-permissive to glioma cell invasion. Thus, glioma etiology remains largely unknown. In this review, we analyze the anatomical and biological basis of gliomagenesis considering neural stem cells, the spatiotemporal diversity of astrocytes, microglia, neurons and glutamate transporters, extracellular matrix and the peritumoral environment. The precise understanding of subpopulations constituting GBM, particularly astrocytes, is not limited to glioma stem cells (GSC) and could help in the understanding of tumor pathophysiology. The anatomical fingerprint is essential for non-invasive assessment of patients' prognosis and correct surgical/radiotherapy planning.

Brain Neoplasms , Glioblastoma , Glioma , Adult , Astrocytes/pathology , Biology , Brain Neoplasms/pathology , Glioblastoma/pathology , Glioma/pathology , Humans , Tumor Microenvironment
J Huntingtons Dis ; 11(1): 25-33, 2022.
Article En | MEDLINE | ID: mdl-35253772

BACKGROUND: In recent years the functions of astrocytes have shifted from conventional supportive roles to also include active roles in altering synapses and engulfment of cellular debris. Recent studies have implicated astrocytes in both protective and pathogenic roles impacting Huntington's disease (HD) progression. OBJECTIVE: The goal of this study is to determine if phagocytosis of cellular debris is compromised in HD striatal astrocytes. METHODS: Primary adult astrocytes were derived from two HD mouse models; the fast-progressing R6/2 and slower progressing Q175. With the use of laser nanosurgery, a single astrocyte was lysed within an astrocyte network. The phagocytic response of astrocytes was observed with phase contrast and by fluorescence microscopy for GFP-LC3 transiently transfected cells. RESULTS: Astrocyte phagocytosis was significantly diminished in primary astrocytes, consistent with the progression of HD in R6/2 and Q175 mouse models. This was defined by the number of astrocytes responding via phagocytosis and by the average number of vesicles formed per cell. GFP-LC3 was found to increasingly localize to phagocytic vesicles over a 20-min imaging period, but not in HD mice, suggesting the involvement of LC3 in astrocyte phagocytosis. CONCLUSION: We demonstrate a progressive decrease in LC3-associated phagocytosis in HD mouse striatal astrocytes.

Huntington Disease , Animals , Astrocytes/pathology , Corpus Striatum/pathology , Disease Models, Animal , Huntington Disease/pathology , Mice , Mice, Transgenic , Phagocytosis
Med Sci Monit ; 28: e933830, 2022 Mar 07.
Article En | MEDLINE | ID: mdl-35250022

BACKGROUND Ischemic cerebrovascular disease leads to the activation and differentiation of neural stem cells (NSCs) into mature neurons and glia cells to repair nerve damage. Astragalus flavone (ASF) has shown its potential role in proliferation and differentiation into dopamine neurons of NSCs. MATERIAL AND METHODS Cerebral infarction models were constructed to determine the effects of ASF on NSCs in vivo and in vitro. RESULTS ASF therapy had the ability to reduce the neurologic function scores and the cerebral infarction volume of the cerebral infarction model. Moreover, ASF was able to increase BrdU-positive cells and promote the expression of Nestin, ß-Tubulin III, and O4, while decreasing the expression of GFAP. qRT-PCR and western blot assays showed ASF promoted the expression of Mash1, Math1, and Ngn2 mRNA and protein in cerebral infarction rats. Meanwhile, ASF (20 µg/ml) was able to increase EdU-positive cells and promote the expression of Nestin, ß-Tubulin III, and O4 of NSCs at day14 in vitro. In normoxia, ASF obviously promoted the expression of Mash1, Ngn1, and Ngn2 mRNA and proteins, but in hypoxia, ASF promoted the expression of Notch1 and Math1 mRNA and proteins and inhibited the expression of Ngn1 and Ngn2 mRNA and proteins. CONCLUSIONS ASF therapy can improve the neurologic functions and reduce the cerebral infarction volume in a cerebral infarction model. Moreover, ASF promoted the proliferation of NSCs and induced differentiation into neurons and oligodendrocytes, which might be involved in regulating factors in Notch signaling.

Cerebral Infarction/pathology , Flavones/pharmacology , Neural Stem Cells/classification , Neurogenesis/drug effects , Animals , Astrocytes/drug effects , Astrocytes/pathology , Cell Differentiation/drug effects , Cell Proliferation , Cells, Cultured , Cerebral Infarction/drug therapy , Disease Models, Animal , Male , Neural Stem Cells/drug effects , Rats , Rats, Wistar , Signal Transduction
CNS Neurosci Ther ; 28(5): 703-713, 2022 05.
Article En | MEDLINE | ID: mdl-35166042

INTRODUCTION: Astrocytes are involved in Parkinson's disease (PD) where they could contribute to α-Synuclein pathology but also to neuroprotection via α-Synuclein clearance. The molecular signature underlying their dual role is still elusive. Given that vitamin D has been recently suggested to be protective in neurodegeneration, the aim of our study was to investigate astrocyte and neuron vitamin D pathway alterations and their correlation with α-Synuclein aggregates (ie, oligomers and fibrils) in human brain obtained from PD patients. METHODS: The expression of vitamin D pathway components CYP27B1, CYP24A1, and VDR was examined in brains obtained from PD patients (Braak stage 6; n = 9) and control subjects (n = 4). We also exploited proximity ligation assay to identified toxic α-Synuclein oligomers in human astrocytes. RESULTS: We found that vitamin D-activating enzyme CYP27B1 identified a subpopulation of astrocytes exclusively in PD patients. CYP27B1 positive astrocytes could display neuroprotective features as they sequester α-Synuclein oligomers and are associated with Lewy body negative neurons. CONCLUSION: The presence of CYP27B1 astrocytes distinguishes PD patients and suggests their contribution to protect neurons and to ameliorate neuropathological traits.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase , Astrocytes , Parkinson Disease , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/metabolism , Astrocytes/pathology , Humans , Lewy Bodies/metabolism , Lewy Bodies/pathology , Neurons/metabolism , Parkinson Disease/pathology , Vitamin D , alpha-Synuclein/metabolism
Biomolecules ; 12(2)2022 01 25.
Article En | MEDLINE | ID: mdl-35204705

Polyamines are organic polycations ubiquitously present in living cells. Polyamines are involved in many cellular processes, and their content in mammalian cells is tightly controlled. Among their function, these molecules modulate the activity of several ion channels. Spermine oxidase, specifically oxidized spermine, is a neuromodulator of several types of ion channel and ionotropic glutamate receptors, and its deregulated activity has been linked to several brain pathologies, including epilepsy. The Dach-SMOX mouse line was generated using a Cre/loxP-based recombination approach to study the complex and critical functions carried out by spermine oxidase and spermine in the mammalian brain. This mouse genetic model overexpresses spermine oxidase in the neocortex and is a chronic model of excitotoxic/oxidative injury and neuron vulnerability to oxidative stress and excitotoxic, since its phenotype revealed to be more susceptible to different acute oxidative insults. In this review, the molecular mechanisms underlined the Dach-SMOX phenotype, linked to reactive astrocytosis, neuron loss, chronic oxidative and excitotoxic stress, and susceptibility to seizures have been discussed in detail. The Dach-SMOX mouse model overexpressing SMOX may help in shedding lights on the susceptibility to epileptic seizures, possibly helping to understand the mechanisms underlying epileptogenesis in vulnerable individuals and contributing to provide new molecular mechanism targets to search for novel antiepileptic drugs.

Astrocytes , Epilepsy , Animals , Astrocytes/pathology , Epilepsy/genetics , Epilepsy/pathology , Mammals , Mice , Mice, Transgenic , Neurons/pathology , Oxidoreductases Acting on CH-NH Group Donors , Seizures/chemically induced , Seizures/genetics , Seizures/pathology
Curr Med Sci ; 42(2): 397-406, 2022 Apr.
Article En | MEDLINE | ID: mdl-35201552

OBJECTIVE: This study aimed to investigate the effects of downregulating astrocyte elevated gene-1 (AEG-1) expression combined with all-trans retinoic acid (ATRA) on vasculogenic mimicry (VM) formation and angiogenesis in glioma. METHODS: U87 glioma cells were transfected with AEG-1 shRNA lentiviral vectors (U87-siAEG-1) and incubated in a medium containing 20 µmol/L ATRA. Matrigel-based tube formation assay was performed to evaluate VM formation, and the cell counting kit-8 (CCK-8) assay was used to analyze the proliferation of glioma cells in vitro. Reverse transcription-quantitative polymerase chain reaction and Western blot analysis were used to investigate the mRNA and protein expression of related genes, respectively. Glioma xenograft models were generated via subcutaneous implantation of glioma cells in nude mice. Tumor-bearing mice received an intraperitoneal injection of ATRA (10 mg/kg per day). Immunohistochemistry was used to evaluate the expression of related genes and the microvessel density (MVD) in glioma xenograft models. CD34/periodic acid-Schiff double staining was performed to detect VM channels in vivo. The volume and weight of tumors were measured, and a tumor growth curve was drawn to evaluate tumor growth. RESULTS: A combination of ATRA intervention and downregulation of AEG-1 expression significantly inhibited the proliferation of glioma cells in vitro and glioma VM formation in vitro and in vivo. It also significantly decreased MVD and inhibited tumor growth. Further, the expression levels of matrix metalloproteinase (MMP)-2, MMP-9, vascular endothelial-cadherin (VE-cadherin), and vascular endothelial growth factor (VEGF) in glioma significantly decreased in vivo and in vivo. CONCLUSION: Hence, a combinatorial approach might be effective in treating glioma through regulating MMP-2, MMP-9, VEGF, and VE-cadherin expression.

Glioma , Matrix Metalloproteinase 9 , Animals , Astrocytes/pathology , Cell Line, Tumor , Down-Regulation , Glioma/drug therapy , Glioma/genetics , Humans , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Nude , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Tretinoin/pharmacology , Vascular Endothelial Growth Factor A/metabolism
Cells ; 11(3)2022 01 24.
Article En | MEDLINE | ID: mdl-35159209

Astrocytes play important roles in the function and survival of neuronal cells. Dysfunctions of astrocytes are associated with numerous disorders and diseases of the nervous system, including motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Human-induced pluripotent stem cell (iPSC)-based approaches are becoming increasingly important for the study of the mechanisms underlying the involvement of astrocytes in non-cell autonomous processes of motor neuron degeneration in ALS. These studies must account for the molecular and functional diversity among astrocytes in different regions of the brain and spinal cord. It is essential that the most pathologically relevant astrocyte preparations are used when investigating non-cell autonomous mechanisms of either upper or lower motor neuron degeneration in ALS. Here, we describe the efficient and streamlined generation of human iPSC-derived astrocytes with molecular and biological properties similar to physiological astrocytes in the ventral spinal cord. These induced astrocytes exhibit spontaneous and ATP-induced calcium transients, and lack signs of overt activation. Human iPSC-derived astrocytes with ventral spinal cord features offer advantages over more generic astrocyte preparations for the study of both ventral spinal cord astrocyte biology and the involvement of astrocytes in mechanisms of lower motor neuron degeneration in ALS.

Amyotrophic Lateral Sclerosis , Induced Pluripotent Stem Cells , Amyotrophic Lateral Sclerosis/pathology , Astrocytes/pathology , Humans , Induced Pluripotent Stem Cells/physiology , Motor Neurons/pathology , Nerve Degeneration/pathology
J Cell Biol ; 221(4)2022 02 09.
Article En | MEDLINE | ID: mdl-35139144

Astrocyte reactivity can directly modulate nervous system function and immune responses during disease and injury. However, the consequence of human astrocyte reactivity in response to specific contexts and within neural networks is obscure. Here, we devised a straightforward bioengineered neural organoid culture approach entailing transcription factor-driven direct differentiation of neurons and astrocytes from human pluripotent stem cells combined with genetically encoded tools for dual cell-selective activation. This strategy revealed that Gq-GPCR activation via chemogenetics in astrocytes promotes a rise in intracellular calcium followed by induction of immediate early genes and thrombospondin 1. However, astrocytes also undergo NF-κB nuclear translocation and secretion of inflammatory proteins, correlating with a decreased evoked firing rate of cocultured optogenetic neurons in suboptimal conditions, without overt neurotoxicity. Altogether, this study clarifies the intrinsic reactivity of human astrocytes in response to targeting GPCRs and delivers a bioengineered approach for organoid-based disease modeling and preclinical drug testing.

Astrocytes/metabolism , Bioengineering , GTP-Binding Protein alpha Subunits, Gq-G11/metabolism , Neurons/metabolism , Organoids/metabolism , Receptors, G-Protein-Coupled/metabolism , Adenosine Triphosphate/pharmacology , Astrocytes/pathology , Calcium/metabolism , Cell Line , Glial Fibrillary Acidic Protein/metabolism , Humans , Inflammation/pathology , Neural Stem Cells/drug effects , Neural Stem Cells/metabolism , Pluripotent Stem Cells/metabolism , Reproducibility of Results , Spheroids, Cellular/drug effects , Spheroids, Cellular/metabolism , Synaptophysin/metabolism
Oxid Med Cell Longev ; 2022: 1764589, 2022.
Article En | MEDLINE | ID: mdl-35154563

Alzheimer's disease (AD) is characterized by the accumulation of ß-amyloid (Aß) plaques and tau neurofibrillary tangles in the brain. Although the exact details of the neuronal protective effect of high-intensity interval training (HIIT) on AD remain unclear, the preclinical phase of AD appears to be the important time point for such intervention. The described experiment investigates the neuroprotective effect of HIIT on AD in APP/PS1 mice. In total, 14 C57BL6 healthy control (C) mice and 14 APP/PS1 AD mice were each randomly assigned into two groups, one that did not participate in HIIT (C and AD groups, respectively) and the other subject to HIIT intervention (control HIIT (CE) and AD HIIT (ADE) groups, respectively). Visualization of hippocampal neuronal cells via HE and Congo red staining showed significant improvement in cell status and a significant reduction in amyloidosis in ADE compared with AD. The results of behavioral analysis show that the HIIT intervention significantly improved cognitive decline and reduced spatial exploration in both the C and AD groups. Immunofluorescence showed that the overall brain and the hippocampus of aged rats in the C and AD groups had different degrees of neuroglial responses and astrocyte GFAP proliferation and hypertrophy, with obvious improvement in the CE and ADE groups after 10 weeks of HIIT intervention. These results show that HIIT significantly improves the status of mitochondrial kinetic proteins and related proteins, with the mechanism differing between the normal aging C and the AD groups. 10 weeks of HIIT improved the imbalance in mitochondrial dynamics present in normal control mice and in AD mice. We conclude that preclinical training intervention has a significant positive effect on the exploratory behavior and cognitive functioning of mice.

Alzheimer Disease/metabolism , Alzheimer Disease/therapy , Astrocytes/metabolism , Astrocytes/pathology , Exercise Therapy/methods , Glial Fibrillary Acidic Protein/metabolism , High-Intensity Interval Training/methods , Mitochondrial Dynamics , Neuroprotection , Physical Conditioning, Animal/methods , Alzheimer Disease/psychology , Animals , Case-Control Studies , Cognition , Cognitive Dysfunction/therapy , Disease Models, Animal , Exploratory Behavior , Hippocampus/metabolism , Hypertrophy , Male , Mice , Mice, Inbred C57BL , Neurons/metabolism , Signal Transduction , Treatment Outcome
Invest Ophthalmol Vis Sci ; 63(2): 1, 2022 02 01.
Article En | MEDLINE | ID: mdl-35103752

Purpose: Sigma 1 receptor (S1R) is expressed in retinal ganglion cells (RGCs) and astrocytes, and its activation is neuroprotective. We evaluated the contribution of S1R within optic nerve head astrocytes (ONHAs) to growth and survival of RGCs in vitro. Methods: Wild-type (WT) RGCs and WT or S1R knockout (S1R KO) ONHAs were cocultured for 2, 4, or 7 days. Total and maximal neurite length, neurite root, and extremity counts were measured. Cell death was measured using a TUNEL assay. Signal transducer and activator of transcription 3 phosphorylation levels were evaluated in ONHA-derived lysates by immunoblotting. Results: The coculture of WT RGCs with WT or S1R KO ONHAs increased the total and maximal neurite length. Neurite root and extremity counts increased at 4 and 7 days when WT RGCs were cocultured with WT or S1R KO ONHAs. At all timepoints, the total and maximal neurite length decreased for WT RGCs in coculture with S1R KO ONHAs compared with WT ONHAs. Root and extremity counts decreased for WT RGCs in coculture with S1R KO ONHAs compared with WT ONHAs at 2 and 7, but not 4 days. RGC apoptosis increased in S1R KO ONHA coculture and S1R KO-conditioned medium, compared with WT ONHA coculture or WT-conditioned medium. S1R KO ONHA-derived lysates showed decreased phosphorylated signal transducer and activator of transcription 3 levels compared with WT ONHA-derived lysates. Conclusions: The absence of S1R within ONHAs has a deleterious effect on RGC neurite growth and RGC survival, reflected in analysis of WT RGC + S1R KO ONHA indirect cocultures. The data suggest that S1R may enhance ganglion cell survival via glia-mediated mechanisms.

Apoptosis , Astrocytes/metabolism , Neuroprotection/physiology , Oxidative Stress , Receptors, sigma/metabolism , Retinal Diseases/metabolism , Retinal Ganglion Cells/metabolism , Animals , Astrocytes/pathology , Blotting, Western , Cell Death , Cell Survival , Cells, Cultured , Disease Models, Animal , In Situ Nick-End Labeling , Mice , Mice, Inbred C57BL , Mice, Knockout , Optic Disk/metabolism , Optic Disk/pathology , Retinal Diseases/pathology , Retinal Ganglion Cells/pathology
Sci Rep ; 12(1): 1796, 2022 02 02.
Article En | MEDLINE | ID: mdl-35110643

An emerging link between circadian clock function and neurodegeneration has indicated a critical role for the molecular clock in brain health. We previously reported that deletion of the core circadian clock gene Bmal1 abrogates clock function and induces cell-autonomous astrocyte activation. Regulation of astrocyte activation has important implications for protein aggregation, inflammation, and neuronal survival in neurodegenerative conditions such as Alzheimer's disease (AD). Here, we investigated how astrocyte activation induced by Bmal1 deletion regulates astrocyte gene expression, amyloid-beta (Aß) plaque-associated activation, and plaque deposition. To address these questions, we crossed astrocyte-specific Bmal1 knockout mice (Aldh1l1-CreERT2;Bmal1fl/fl, termed BMAL1 aKO), to the APP/PS1-21 and the APPNL-G-F models of Aß accumulation. Transcriptomic profiling showed that BMAL1 aKO induced a unique transcriptional profile affecting genes involved in both the generation and elimination of Aß. BMAL1 aKO mice showed exacerbated astrocyte activation around Aß plaques and altered gene expression. However, this astrogliosis did not affect plaque accumulation or neuronal dystrophy in either model. Our results demonstrate that the striking astrocyte activation induced by Bmal1 knockout does not influence Aß deposition, which indicates that the effect of astrocyte activation on plaque pathology in general is highly dependent on the molecular mechanism of activation.

ARNTL Transcription Factors/deficiency , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Astrocytes/metabolism , Biological Clocks , Circadian Rhythm , Plaque, Amyloid , ARNTL Transcription Factors/genetics , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Peptides/genetics , Animals , Astrocytes/pathology , Biological Clocks/genetics , Circadian Rhythm/genetics , Disease Models, Animal , Female , Gene Expression Regulation , Male , Mice, Inbred C57BL , Mice, Knockout , Transcription, Genetic , Transcriptome
Int J Mol Sci ; 23(4)2022 Feb 11.
Article En | MEDLINE | ID: mdl-35216123

Aging is the greatest risk factor for late-onset Alzheimer's disease (LOAD), which accounts for >95% of Alzheimer's disease (AD) cases. The mechanism underlying the aging-related susceptibility to LOAD is unknown. Cellular senescence, a state of permanent cell growth arrest, is believed to contribute importantly to aging and aging-related diseases, including AD. Senescent astrocytes, microglia, endothelial cells, and neurons have been detected in the brain of AD patients and AD animal models. Removing senescent cells genetically or pharmacologically ameliorates ß-amyloid (Aß) peptide and tau-protein-induced neuropathologies, and improves memory in AD model mice, suggesting a pivotal role of cellular senescence in AD pathophysiology. Nonetheless, although accumulated evidence supports the role of cellular senescence in aging and AD, the mechanisms that promote cell senescence and how senescent cells contribute to AD neuropathophysiology remain largely unknown. This review summarizes recent advances in this field. We believe that the removal of senescent cells represents a promising approach toward the effective treatment of aging-related diseases, such as AD.

Aging/pathology , Alzheimer Disease/pathology , Cellular Senescence/physiology , Animals , Astrocytes/pathology , Brain/pathology , Humans , Neurons/pathology
Neurol Sci ; 43(4): 2895-2897, 2022 Apr.
Article En | MEDLINE | ID: mdl-35146565

OBJECTIVE: We describe an unusual case of corticosteroid-responsive autoimmune meningoencephalomyelitis with linear perivascular gadolinium enhancement but in the absence of anti- glial fibrillary acidic protein (GFAP) antibodies (ABs) in the cerebral spinal fluid (CSF). METHODS: The patient's clinical symptoms, brain magnetic resonance imaging (MRI) features, serum and CSF analysis and treatment were reviewed. RESULTS: A 47-year-old female experienced a subacute course with bilateral lower limbs weakness, unsteady walking, and dysuria. Brain MRI revealed typical radial perivascular gadolinium enhancement extending from the lateral ventricles to the white matter; MRI spine revealed lesions distributed in the entire spinal cord. Immunohistochemical staining of a brain biopsy revealed CD3+ T cells and CD20+ B cells cuffing around brain vessels, accompanied by CD68+ macrophages. CSF was negative for anti-GFAP ABs while serum was positive for anti-GFAP ABs (1:100). The patient responded well to corticosteroid. CONCLUSIONS: There are no uniform diagnostic criteria for autoimmune GFAP astrocytopathy. Our case suggested the importance of typical MRI findings in the diagnosis of this rare disease. Early treatments are very important to alleviate symptoms.

Autoimmune Diseases of the Nervous System , Glial Fibrillary Acidic Protein , Adrenal Cortex Hormones/therapeutic use , Astrocytes/pathology , Autoantibodies , Autoimmune Diseases of the Nervous System/diagnostic imaging , Autoimmune Diseases of the Nervous System/drug therapy , B-Lymphocytes , Biopsy , Brain/diagnostic imaging , Brain/pathology , Contrast Media , Female , Gadolinium , Humans , Macrophages , Middle Aged , T-Lymphocytes
Int J Mol Sci ; 23(3)2022 Jan 20.
Article En | MEDLINE | ID: mdl-35163053

Astrocytes and microglia are the first cells to react to neurodegeneration, e.g., in Alzheimer's disease (AD); however, the data on changes in glial support during the most common (sporadic) type of the disease are sparse. Using senescence-accelerated OXYS rats, which simulate key characteristics of sporadic AD, and Wistar rats (parental normal strain, control), we investigated hippocampal neurogenesis and glial changes during AD-like pathology. Using immunohistochemistry, we showed that the early stage of the pathology is accompanied by a lower intensity of neurogenesis and decreased astrocyte density in the dentate gyrus. The progressive stage is concurrent with reactive astrogliosis and microglia activation, as confirmed by increased cell densities and by the acquisition of cell-specific gene expression profiles, according to transcriptome sequencing data. Besides, here, we continued to analyze the anti-AD effects of prolonged supplementation with mitochondria-targeted antioxidant SkQ1. The antioxidant did not affect neurogenesis, partly normalized the gene expression profile of astrocytes and microglia, and shifted the resting/activated microglia ratio toward a decrease in the activated-cell density. In summary, both astrocytes and microglia are more vulnerable to AD-associated neurodegeneration in the CA3 area than in other hippocampal areas; SkQ1 had an anti-inflammatory effect and is a promising modality for AD prevention and treatment.

Alzheimer Disease/diet therapy , Alzheimer Disease/pathology , Dentate Gyrus/pathology , Plastoquinone/analogs & derivatives , Alzheimer Disease/etiology , Alzheimer Disease/genetics , Animals , Astrocytes/chemistry , Astrocytes/drug effects , Astrocytes/pathology , Dentate Gyrus/chemistry , Dentate Gyrus/drug effects , Dietary Supplements , Disease Models, Animal , Gene Expression Profiling , Gene Expression Regulation/drug effects , Male , Mitochondria/drug effects , Mitochondria/genetics , Plastoquinone/administration & dosage , Plastoquinone/pharmacology , Rats , Rats, Wistar
Sci Rep ; 12(1): 1710, 2022 02 02.
Article En | MEDLINE | ID: mdl-35110605

The study is aimed at elucidating the effect of selenium nanoparticles (SeNPs) on the death of cells in the primary culture of mouse cerebral cortex during oxygen and glucose deprivation (OGD). A primary cell culture of the cerebral cortex containing neurons and astrocytes was subjected to OGD and reoxygenation to simulate cerebral ischemia-like conditions in vitro. To evaluate the neuroprotective effect of SeNPs, cortical astrocytes and neurons were incubated for 24 h with SeNPs, and then subjected to 2-h OGD, followed by 24-h reoxygenation. Vitality tests, fluorescence microscopy, and real-time PCR have shown that incubation of primary cultured neurons and astrocytes with SeNPs at concentrations of 2.5-10 µg/ml under physiological conditions has its own characteristics depending on the type of cells (astrocytes or neurons) and leads to a dose-dependent increase in apoptosis. At low concentration SeNPs (0.5 µg/ml), on the contrary, almost completely suppressed the processes of basic necrosis and apoptosis. Both high (5 µg/ml) and low (0.5 µg/ml) concentrations of SeNPs, added for 24 h to the cells of cerebral cortex, led to an increase in the expression level of genes Bcl-2, Bcl-xL, Socs3, while the expression of Bax was suppressed. Incubation of the cells with 0.5 µg/ml SeNPs led to a decrease in the expression of SelK and SelT. On the contrary, 5 µg/ml SeNPs caused an increase in the expression of SelK, SelN, SelT, SelP. In the ischemic model, after OGD/R, there was a significant death of brain cells by the type of necrosis and apoptosis. OGD/R also led to an increase in mRNA expression of the Bax, SelK, SelN, and SelT genes and suppression of the Bcl-2, Bcl-xL, Socs3, SelP genes. Pre-incubation of cell cultures with 0.5 and 2.5 µg/ml SeNPs led to almost complete inhibition of OGD/R-induced necrosis and greatly reduced apoptosis. Simultaneously with these processes we observed suppression of caspase-3 activation. We hypothesize that the mechanisms of the protective action of SeNPs involve the activation of signaling cascades recruiting nuclear factors Nrf2 and SOCS3/STAT3, as well as the activation of adaptive pathways of ESR signaling of stress arising during OGD and involving selenoproteins SelK and SelT, proteins of the Bcl-2 family ultimately leading to inactivation of caspase-3 and inhibition of apoptosis. Thus, our results demonstrate that SeNPs can act as neuroprotective agents in the treatment of ischemic brain injuries.

Apoptosis/drug effects , Astrocytes/drug effects , Brain Ischemia/drug therapy , Cerebral Cortex/drug effects , Glucose/deficiency , Nanoparticles , Neurons/drug effects , Neuroprotective Agents/pharmacology , Selenium Compounds/pharmacology , Animals , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Astrocytes/metabolism , Astrocytes/pathology , Brain Ischemia/genetics , Brain Ischemia/metabolism , Brain Ischemia/pathology , Cell Hypoxia , Cells, Cultured , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Coculture Techniques , Female , Male , Mice , Necrosis , Neurons/metabolism , Neurons/pathology , Primary Cell Culture , Selenoproteins/genetics , Selenoproteins/metabolism
Metab Brain Dis ; 37(3): 801-805, 2022 03.
Article En | MEDLINE | ID: mdl-35032278

Alzheimer's disease (AD) is a complex neurodegenerative disorder that leads to severe impairments in cognitive functions including memory and learning. An improved kinetic model is proposed here to understand the pathogenesis of AD in particular the role of glial cells in the presence of amyloid plaques and neurofibrillary tangles (NFTs). The kinetic model describes the production of activated microglia and astroglia. It involves two rate equations and incorporates the dual role of these glial cells which can function as neuroprotective and as neurotoxic cells. Examination of the steady state solutions of the model predicts an increase in population of these glial cells as (AD) progresses, and that this continues to increase linearly even after the amyloid population has reached a plateau.This is in agreement with experimental data. Limiting AD to the effect of amyloid peptides alone is incorrect and the role of neurofibrillary tangles, clearance rate of dead neurons and neuroinflammation from glial cells are vital and must be included in understanding the pathogenesis of AD. The study shows that increasing the clearance of dead neurons and use of any method to deactivate the glial cells will diminish the progression of AD.

Alzheimer Disease , Alzheimer Disease/pathology , Amyloid beta-Peptides , Astrocytes/pathology , Humans , Microglia/pathology , Neurofibrillary Tangles/pathology , Plaque, Amyloid/pathology
Toxins (Basel) ; 14(1)2022 01 10.
Article En | MEDLINE | ID: mdl-35051025

Chronic exposure to the mycotoxin deoxynivalenol (DON) from grain-based food and feed affects human and animal health. Known consequences include entereopathogenic and immunotoxic defects; however, the neurotoxic potential of DON has only come into focus more recently due to the observation of behavioural disorders in exposed farm animals. DON can cross the blood-brain barrier and interfere with the homeostasis/functioning of the nervous system, but the underlying mechanisms of action remain elusive. Here, we have investigated the impact of DON on mouse astrocyte and microglia cell lines, as well as on primary hippocampal cultures by analysing different toxicological endpoints. We found that DON has an impact on the viability of both glial cell types, as shown by a significant decrease of metabolic activity, and a notable cytotoxic effect, which was stronger in the microglia. In astrocytes, DON caused a G1 phase arrest in the cell cycle and a decrease of cyclic-adenosine monophosphate (cAMP) levels. The pro-inflammatory cytokine tumour necrosis factor (TNF)-α was secreted in the microglia in response to DON exposure. Furthermore, the intermediate filaments of the astrocytic cytoskeleton were disturbed in primary hippocampal cultures, and the dendrite lengths of neurons were shortened. The combined results indicated DON's considerable potential to interfere with the brain cell physiology, which helps explain the observed in vivo neurotoxicological effects.

Astrocytes/drug effects , Hippocampus/drug effects , Microglia/drug effects , Neurotoxins/pharmacology , Trichothecenes/pharmacology , Animals , Astrocytes/pathology , Cell Line , Hippocampus/physiopathology , Mice , Mice, Inbred C57BL , Microglia/pathology
Mult Scler Relat Disord ; 58: 103512, 2022 Feb.
Article En | MEDLINE | ID: mdl-35066273

BACKGROUND: Autoimmune glial fibrillary acidic protein astrocytopathy (AGA) is a relatively novel disease. The early diagnosis of this inflammatory central nervous system (CNS) disorder remains challenging. OBJECTIVES: We aimed to explore the imaging manifestations and evolution of AGA to facilitate its successful diagnosis and monitoring. METHODS: From January 2016 to January 2021, a total of 15 consecutive patients, who were hospitalised in our institution and confirmed AGA clinically, were enrolled in this IRB-approved retrospective study. All clinical features and MRI manifestations were analysed cross-sectionally and longitudinally. Distribution, morphology, enhancement pattern and evolution of AGA lesions were assessed visually and evaluated semi-quantitatively by calculating the burden of disease (BOD) and the signal intensity ratio (SIR). Chi-square, Mann-Whitney U and Kolmogorov-Smirnov Z tests were performed for lesion patterns' statistical comparison. RESULTS: Fever, limb weakness, headache and cognitive impairment were the most common symptoms in AGA. 14 patients were initially misdiagnosed as infection (n = 9), demyelination (n = 4) or infarction (n = 1). The median time interval from onset to confirmed AGA diagnosis was 46 days. Both BOD and SIR progressed in the natural course and were relieved after immunotherapy on MRI. Meningeal enhancement, one of the most common MRI findings in patients with AGA (100%), relieved faster than intraparenchymal enhancement (p <0.001) and peri­ventricular radial linear (PVRL) enhancement (p <0.001) after the initiation of immunotherapy. Non-enhanced lesions had lower BOD (p <0.001) and were relieved slower (p <0.001) than enhanced ones. CONCLUSIONS: MRI provides valuable neuroradiological indicators for the diagnosis and follow-up of AGA. The CNS enhancement patterns (meningeal / PVRL) facilitate the early diagnosis and treatment response monitoring of AGA, while lesion manifestation in the spinal cord contributes to the follow-up. The evolution inconsistency of AGA lesions in different regions may be attributed to the discrepancy within glial fibrillary acidic protein subtypes.

Autoimmune Diseases of the Nervous System , Astrocytes/pathology , Autoantibodies/metabolism , Autoimmune Diseases of the Nervous System/diagnostic imaging , Autoimmune Diseases of the Nervous System/therapy , Cross-Sectional Studies , Glial Fibrillary Acidic Protein , Humans , Longitudinal Studies , Magnetic Resonance Imaging , Retrospective Studies
Invest Ophthalmol Vis Sci ; 63(1): 7, 2022 01 03.
Article En | MEDLINE | ID: mdl-34989761

Purpose: Dry eye-induced chronic ocular pain is also called ocular neuropathic pain. However, details of the pathogenic mechanism remain unknown. The purpose of this study was to elucidate the pathogenic mechanism of dry eye-induced chronic pain in the anterior eye area and develop a pathophysiology-based therapeutic strategy. Methods: We used a rat dry eye model with lacrimal gland excision (LGE) to elucidate the pathogenic mechanism of ocular neuropathic pain. Corneal epithelial damage, hypersensitivity, and hyperalgesia were evaluated on the LGE side and compared with the sham surgery side. We analyzed neuronal activity, microglial and astrocytic activity, α2δ-1 subunit expression, and inhibitory interneurons in the trigeminal nucleus. We also evaluated the therapeutic effects of ophthalmic treatment and chronic pregabalin administration on dry eye-induced ocular neuropathic pain. Results: Dry eye caused hypersensitivity and hyperalgesia on the LGE side. In the trigeminal nucleus of the LGE side, neuronal hyperactivation, transient activation of microglia, persistent activation of astrocytes, α2δ-1 subunit upregulation, and reduced numbers of inhibitory interneurons were observed. Ophthalmic treatment alone did not improve hyperalgesia. In contrast, continuous treatment with pregabalin effectively ameliorated hypersensitivity and hyperalgesia and normalized neural activity, α2δ-1 subunit upregulation, and astrocyte activation. Conclusions: These results suggest that dry eye-induced hypersensitivity and hyperalgesia are caused by central sensitization in the trigeminal nucleus with upregulation of the α2δ-1 subunit. Here, we showed that pregabalin is effective for treating dry eye-induced ocular neuropathic pain even after chronic pain has been established.

Analgesics/administration & dosage , Disease Models, Animal , Dry Eye Syndromes/physiopathology , Eye Pain/physiopathology , Pregabalin/administration & dosage , Administration, Ophthalmic , Animals , Astrocytes/pathology , Calcium Channels, L-Type/metabolism , Chronic Disease , Cornea/innervation , Dry Eye Syndromes/drug therapy , Eye Pain/drug therapy , Hyaluronic Acid/administration & dosage , Hyperalgesia/drug therapy , Hyperalgesia/physiopathology , Male , Microglia/pathology , Neuralgia/drug therapy , Neuralgia/physiopathology , Neurons/metabolism , Neurons/pathology , Ophthalmic Solutions , Rats , Rats, Sprague-Dawley , Trigeminal Nerve/metabolism , Trigeminal Nerve/pathology