2,116 results on '"Glial Fibrillary Acidic Protein genetics"'
Search Results
2. Co-occurrence of glial fibrillary acidic protein astrocytopathy in a patient with Leber's hereditary optic neuropathy due to DNAJC30 mutations.
- Author
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Giannoccaro MP, Morelli L, Ricciardiello F, Donadio V, Bartiromo F, Tonon C, Carbonelli M, Amore G, Carelli V, Liguori R, and La Morgia C
- Subjects
- Humans, Astrocytes pathology, Astrocytes metabolism, Male, HSP40 Heat-Shock Proteins genetics, Adult, Female, Optic Atrophy, Hereditary, Leber genetics, Optic Atrophy, Hereditary, Leber complications, Glial Fibrillary Acidic Protein genetics, Mutation
- Abstract
Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by visual loss, and rarely associated with extraocular manifestations including multiple sclerosis-like lesions. The association of LHON and neuromyelitis optica spectrum disorders has rarely been reported. Here is reported a case of glial fibrillary acidic protein astrocytopathy presenting with area postrema syndrome in a patient with previously diagnosed recessive LHON due to mutations in the nuclear gene DNAJC30. This case emphasizes the necessity of extensive investigations for other treatable conditions in patients with LHON and otherwise unexplained extraocular involvement and the possibility that also visual symptoms can respond to immune therapy., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)
- Published
- 2024
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3. Tirzepatide shows neuroprotective effects via regulating brain glucose metabolism in APP/PS1 mice.
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Yang S, Zhao X, Zhang Y, Tang Q, Li Y, Du Y, and Yu P
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- Animals, Mice, Disease Models, Animal, Brain metabolism, Brain drug effects, Mice, Transgenic, Glucagon-Like Peptide-1 Receptor metabolism, Glucagon-Like Peptide-1 Receptor genetics, Amyloid beta-Protein Precursor metabolism, Amyloid beta-Protein Precursor genetics, Male, Amyloid beta-Peptides metabolism, Receptors, Gastrointestinal Hormone metabolism, Receptors, Gastrointestinal Hormone genetics, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Activating Transcription Factor 4, Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Alzheimer Disease pathology, Neuroprotective Agents pharmacology, Glucose metabolism
- Abstract
Tirzepatide (LY3298176), a GLP-1 and GIP receptor agonist, is fatty-acid-modified and 39-amino acid linear peptide, which ameliorates learning and memory impairment in diabetic rats. However, the specific molecular mechanism remains unknown. In the present study, we investigated the role of tirzepatide in the neuroprotective effects in Alzheimer's disease (AD) model mice. Tirzepatide was administrated intraperitoneal (i.p.) APP/PS1 mice for 8 weeks with at 10 nmol/kg once-weekly, it significantly decreased the levels of GLP-1R, and GFAP protein expression and amyloid plaques in the cortex, it also lowered neuronal apoptosis induced by amyloid-β (Aβ), but did not affect the anxiety and cognitive function in APP/PS1 mice. Moreover, tirzepatide reduced the blood glucose levels and increased the mRNA expression of GLP-1R, SACF1, ATF4, Glu2A, and Glu2B in the hypothalamus of APP/PS1 mice. Tirzepatide increased the mRNA expression of glucose transporter 1, hexokinase, glucose-6-phosphate dehydrogenase, and phosphofructokinase in the cortex. Lastly, tirzepatide improved the energetic metabolism by regulated reactive oxygen species production and mitochondrial membrane potential caused by Aβ, thereby decreasing mitochondrial function and ATP levels in astrocytes through GLP-1R. These results provide valuable insights into the mechanism of brain glucose metabolism and mitochondrial function of tirzepatide, presenting potential strategies for AD treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing or conflicting interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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4. Spatiotemporal Dysregulation of Neuron-Glia Related Genes and Pro-/Anti-Inflammatory miRNAs in the 5xFAD Mouse Model of Alzheimer's Disease.
- Author
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Ianni M, Corraliza-Gomez M, Costa-Coelho T, Ferreira-Manso M, Inteiro-Oliveira S, Alemãn-Serrano N, Sebastião AM, Garcia G, Diógenes MJ, and Brites D
- Subjects
- Animals, Mice, Mice, Transgenic, Receptors, Immunologic genetics, Receptors, Immunologic metabolism, Gene Expression Regulation, Membrane Glycoproteins genetics, Membrane Glycoproteins metabolism, Prefrontal Cortex metabolism, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Male, MicroRNAs genetics, MicroRNAs metabolism, Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease pathology, Disease Models, Animal, Neurons metabolism, Neuroglia metabolism, Hippocampus metabolism
- Abstract
Alzheimer's disease (AD), the leading cause of dementia, is a multifactorial disease influenced by aging, genetics, and environmental factors. miRNAs are crucial regulators of gene expression and play significant roles in AD onset and progression. This exploratory study analyzed the expression levels of 28 genes and 5 miRNAs (miR-124-3p, miR-125b-5p, miR-21-5p, miR-146a-5p, and miR-155-5p) related to AD pathology and neuroimmune responses using RT-qPCR. Analyses were conducted in the prefrontal cortex (PFC) and the hippocampus (HPC) of the 5xFAD mouse AD model at 6 and 9 months old. Data highlighted upregulated genes encoding for glial fibrillary acidic protein ( Gfap ), triggering receptor expressed on myeloid cells ( Trem2 ) and cystatin F ( Cst7 ), in the 5xFAD mice at both regions and ages highlighting their roles as critical disease players and potential biomarkers. Overexpression of genes encoding for CCAAT enhancer-binding protein alpha ( Cebpa ) and myelin proteolipid protein ( Plp ) in the PFC, as well as for BCL2 apoptosis regulator ( Bcl2 ) and purinergic receptor P2Y12 ( P2yr12 ) in the HPC, together with upregulated microRNA(miR)-146a-5p in the PFC, prevailed in 9-month-old animals. miR-155 positively correlated with miR-146a and miR-21 in the PFC, and miR-125b positively correlated with miR-155, miR-21, while miR-146a in the HPC. Correlations between genes and miRNAs were dynamic, varying by genotype, region, and age, suggesting an intricate, disease-modulated interaction between miRNAs and target pathways. These findings contribute to our understanding of miRNAs as therapeutic targets for AD, given their multifaceted effects on neurons and glial cells.
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- 2024
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5. Increased Expression of the Neuropeptides PACAP/VIP in the Brain of Mice with CNS Targeted Production of IL-6 Is Mediated in Part by Trans-Signalling.
- Author
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Castorina A, Scheller J, Keay KA, Marzagalli R, Rose-John S, and Campbell IL
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- Animals, Mice, Astrocytes metabolism, Humans, Mice, Transgenic, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Central Nervous System metabolism, STAT3 Transcription Factor metabolism, STAT3 Transcription Factor genetics, Male, Mice, Inbred C57BL, Pituitary Adenylate Cyclase-Activating Polypeptide metabolism, Pituitary Adenylate Cyclase-Activating Polypeptide genetics, Interleukin-6 metabolism, Interleukin-6 genetics, Vasoactive Intestinal Peptide metabolism, Vasoactive Intestinal Peptide genetics, Signal Transduction, Brain metabolism
- Abstract
Inflammation with expression of interleukin 6 (IL-6) in the central nervous system (CNS) occurs in several neurodegenerative/neuroinflammatory conditions and may cause neurochemical changes to endogenous neuroprotective systems. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are two neuropeptides with well-established protective and anti-inflammatory properties. Yet, whether PACAP and VIP levels are altered in mice with CNS-restricted, astrocyte-targeted production of IL-6 (GFAP-IL6) remains unknown. In this study, PACAP/VIP levels were assessed in the brain of GFAP-IL6 mice. In addition, we utilised bi-genic GFAP-IL6 mice carrying the human sgp130-Fc transgene (termed GFAP-IL6/sgp130Fc mice) to determine whether trans-signalling inhibition rescued PACAP/VIP changes in the CNS. Transcripts and protein levels of PACAP and VIP, as well as their receptors PAC1, VPAC1 and VPAC2, were significantly increased in the cerebrum and cerebellum of GFAP-IL6 mice vs. wild type (WT) littermates. These results were paralleled by a robust activation of the JAK/STAT3, NF-κB and ERK1/2MAPK pathways in GFAP-IL6 mice. In contrast, co-expression of sgp130Fc in GFAP-IL6/sgp130Fc mice reduced VIP expression and activation of STAT3 and NF-κB pathways, but it failed to rescue PACAP, PACAP/VIP receptors and Erk1/2MAPK phosphorylation. We conclude that forced expression of IL-6 in astrocytes induces the activation of the PACAP/VIP neuropeptide system in the brain, which is only partly modulated upon IL-6 trans-signalling inhibition. Increased expression of PACAP/VIP neuropeptides and receptors may represent a homeostatic response of the CNS to an uncontrolled IL-6 synthesis and its neuroinflammatory consequences.
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- 2024
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6. FTY720/Fingolimod mitigates paclitaxel-induced Sparcl1-driven neuropathic pain and breast cancer progression.
- Author
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Singh SK, Weigel C, Brown RDR, Green CD, Tuck C, Salvemini D, and Spiegel S
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- Animals, Mice, Female, Calcium-Binding Proteins metabolism, Calcium-Binding Proteins genetics, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms pathology, Astrocytes metabolism, Astrocytes drug effects, Extracellular Matrix Proteins metabolism, Extracellular Matrix Proteins genetics, Cell Line, Tumor, Sphingosine-1-Phosphate Receptors metabolism, Humans, Disease Progression, Antineoplastic Agents, Phytogenic pharmacology, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Fingolimod Hydrochloride pharmacology, Paclitaxel pharmacology, Neuralgia chemically induced, Neuralgia drug therapy, Neuralgia metabolism, Neuralgia pathology
- Abstract
Paclitaxel is among the most active chemotherapy drugs for the aggressive triple negative breast cancer (TNBC). Unfortunately, it often induces painful peripheral neuropathy (CIPN), a major debilitating side effect. Here we demonstrate that in naive and breast tumor-bearing immunocompetent mice, a clinically relevant dose of FTY720/Fingolimod that targets sphingosine-1-phosphate receptor 1 (S1PR1), alleviated paclitaxel-induced neuropathic pain. FTY720 also significantly attenuated paclitaxel-stimulated glial fibrillary acidic protein (GFAP), a marker for activated astrocytes, and expression of the astrocyte-secreted synaptogenic protein Sparcl1/Hevin, a key regulator of synapse formation. Notably, the formation of excitatory synapses containing VGluT2 in the spinal cord dorsal horn induced by paclitaxel was also inhibited by FTY720 treatment, supporting the involvement of astrocytes and Sparcl1 in CIPN. Furthermore, in this TNBC mouse model that mimics human breast cancer, FTY720 administration also enhanced the anti-tumor effects of paclitaxel, leading to reduced tumor progression and lung metastasis. Taken together, our findings suggest that targeting the S1P/S1PR1 axis with FTY720 is a multipronged approach that holds promise as a therapeutic strategy for alleviating both CIPN and enhancing the efficacy of chemotherapy in TNBC treatment., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
- Published
- 2024
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7. [Embryonal tumor with multilayered rosettes: a clinicopathological analysis of three cases].
- Author
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Lu LZ, Bai YX, Meng J, Zhang Y, Xie SG, and Zhang LH
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- Humans, Male, Female, Child, Preschool, Retrospective Studies, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Nestin metabolism, Nestin genetics, Parietal Lobe pathology, Parietal Lobe metabolism, Nerve Tissue Proteins metabolism, Nerve Tissue Proteins genetics, Chromosomal Proteins, Non-Histone metabolism, Chromosomal Proteins, Non-Histone genetics, Brain Stem Neoplasms pathology, Brain Stem Neoplasms genetics, Brain Stem Neoplasms metabolism, Brain Stem Neoplasms surgery, Transcription Factors metabolism, Transcription Factors genetics, SMARCB1 Protein metabolism, SMARCB1 Protein genetics, Frontal Lobe pathology, Frontal Lobe metabolism, Rosette Formation, Follow-Up Studies, Ki-67 Antigen metabolism, DNA-Binding Proteins metabolism, DNA-Binding Proteins genetics, Brain Neoplasms pathology, Brain Neoplasms metabolism, Brain Neoplasms genetics, RNA-Binding Proteins metabolism, RNA-Binding Proteins genetics
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- 2024
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8. KLOTHO KL-VS heterozygosity is associated with diminished age-related neuroinflammation, neurodegeneration, and synaptic dysfunction in older cognitively unimpaired adults.
- Author
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Driscoll IF, Lose S, Ma Y, Bendlin BB, Gallagher C, Johnson SC, Asthana S, Hermann B, Sager MA, Blennow K, Zetterberg H, Carlsson C, Kollmorgen G, Quijano-Rubio C, Dubal D, and Okonkwo OC
- Subjects
- Humans, Female, Male, Middle Aged, Aged, Glucuronidase genetics, Glucuronidase cerebrospinal fluid, Interleukin-6 cerebrospinal fluid, Interleukin-6 genetics, Receptors, Immunologic genetics, Neuroinflammatory Diseases genetics, Neuroinflammatory Diseases cerebrospinal fluid, S100 Calcium Binding Protein beta Subunit cerebrospinal fluid, S100 Calcium Binding Protein beta Subunit genetics, Cohort Studies, Glial Fibrillary Acidic Protein cerebrospinal fluid, Glial Fibrillary Acidic Protein genetics, Alzheimer Disease cerebrospinal fluid, Alzheimer Disease genetics, alpha-Synuclein cerebrospinal fluid, alpha-Synuclein genetics, Neurogranin cerebrospinal fluid, Neurogranin genetics, Membrane Glycoproteins, Klotho Proteins, Biomarkers cerebrospinal fluid, Aging genetics, Chitinase-3-Like Protein 1 cerebrospinal fluid, Chitinase-3-Like Protein 1 genetics, Heterozygote
- Abstract
Introduction: We examined whether the aging suppressor KLOTHO gene's functionally advantageous KL-VS variant (KL-VS heterozygosity [KL-VS
HET ]) confers resilience against deleterious effects of aging indexed by cerebrospinal fluid (CSF) biomarkers of neuroinflammation (interleukin-6 [IL-6], S100 calcium-binding protein B [S100B], triggering receptor expressed on myeloid cells [sTREM2], chitinase-3-like protein 1 [YKL-40], glial fibrillary acidic protein [GFAP]), neurodegeneration (total α-synuclein [α-Syn], neurofilament light chain protein), and synaptic dysfunction (neurogranin [Ng])., Methods: This Alzheimer disease risk-enriched cohort consisted of 454 cognitively unimpaired adults (Mage = 61.5 ± 7.75). Covariate-adjusted multivariate regression examined relationships between age (mean-split[age ≥ 62]) and CSF biomarkers (Roche/NeuroToolKit), and whether they differed between KL-VSHET (N = 122) and non-carriers (KL-VSNC ; N = 332)., Results: Older age was associated with a poorer biomarker profile across all analytes (Ps ≤ 0.03). In age-stratified analyses, KL-VSNC exhibited this same pattern (Ps ≤ 0.05) which was not significant for IL-6, S100B, Ng, and α-Syn (Ps ≥ 0.13) in KL-VSHET . Although age-related differences in GFAP, sTREM2, and YKL-40 were evident for both groups (Ps ≤ 0.01), the effect magnitude was markedly stronger for KL-VSNC ., Discussion: Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults were attenuated in KL-VSHET ., Highlights: Older age was associated with poorer profiles across all cerebrospinal fluid biomarkers of neuroinflammation, neurodegeneration, and synaptic dysfunction. KLOTHO KL-VS non-carriers exhibit this same pattern, which is does not significantly differ between younger and older KL-VS heterozygotes for interleukin-6, S100 calcium-binding protein B, neurogranin, and total α-synuclein. Although age-related differences in glial fibrillary acidic protein, triggering receptor expressed on myeloid cells, and chitinase-3-like protein 1 are evident for both KL-VS groups, the magnitude of the effect is markedly stronger for KL-VS non-carriers. Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults are attenuated in KL-VS heterozygotes., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)- Published
- 2024
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9. Effect of curcumin-donepezil combination on spatial memory, astrocyte activation, and cholinesterase expressions in brain of scopolamine-treated rats.
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Ogunsuyi OB, Ogunruku OO, Umar HI, and Oboh G
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- Animals, Rats, Male, Brain drug effects, Brain metabolism, Rats, Wistar, Oxidative Stress drug effects, Cholinesterases metabolism, Adenosine Deaminase metabolism, Adenosine Deaminase genetics, Butyrylcholinesterase metabolism, Butyrylcholinesterase genetics, Nitric Oxide metabolism, Cholinesterase Inhibitors pharmacology, Cholinesterase Inhibitors administration & dosage, Donepezil pharmacology, Curcumin pharmacology, Curcumin administration & dosage, Scopolamine pharmacology, Astrocytes drug effects, Astrocytes metabolism, Spatial Memory drug effects, Acetylcholinesterase metabolism, Acetylcholinesterase genetics, Hippocampus drug effects, Hippocampus metabolism, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics
- Abstract
Background: The study investigated the effect of co-administration of curcumin and donepezil on several markers of cognitive function (such as spatial memory, astrocyte activation, cholinesterase expressions) in the brain cortex and hippocampus of scopolamine-treated rats., Method and Results: For seven consecutive days, a pre-treatment of curcumin (50 mg/kg) and/or donepezil (2.5 mg/kg) was administered. On the seventh day, scopolamine (1 mg/kg) was administered to elicit cognitive impairment, 30 min before memory test was conducted. This was followed by evaluating changes in spatial memory, cholinesterase, and adenosine deaminase (ADA) activities, as well as nitric oxide (NO) level were determined. Additionally, RT-qPCR for glial fibrillary acidic protein (GFAP) and cholinesterase gene expressions was performed in the brain cortex and hippocampus. Also, GFAP immunohistochemistry of the brain tissues for neuronal injury were performed in the brain cortex and hippocampus. In comparison to the control group, rats given scopolamine had impaired memory, higher levels of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ADA activities, as well as elevated markers of oxidative stress. In addition to enhanced GFAP immunoreactivity, there was also overexpression of the GFAP and BChE genes in the brain tissues. The combination of curcumin and donepezil was, however, observed to better ameliorate these impairments in comparison to the donepezil-administered rat group., Conclusion: Hence, this evidence provides more mechanisms to support the hypothesis that the concurrent administration of curcumin and donepezil mitigates markers of cognitive dysfunction in scopolamine-treated rat model., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)
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- 2024
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10. Fluid Biomarkers in Individuals at Risk for Genetic Prion Disease up to Disease Conversion.
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Vallabh SM, Mortberg MA, Allen SW, Kupferschmid AC, Kivisakk P, Hammerschlag BL, Bolling A, Trombetta BA, Devitte-McKee K, Ford AM, Sather LE, Duffy G, Rivera A, Gerber J, McManus AJ, Minikel EV, and Arnold SE
- Subjects
- Humans, Female, Male, Middle Aged, Longitudinal Studies, Adult, tau Proteins cerebrospinal fluid, tau Proteins blood, Neurofilament Proteins cerebrospinal fluid, Neurofilament Proteins blood, Heterozygote, Glial Fibrillary Acidic Protein blood, Glial Fibrillary Acidic Protein cerebrospinal fluid, Glial Fibrillary Acidic Protein genetics, Disease Progression, alpha-Synuclein cerebrospinal fluid, alpha-Synuclein genetics, alpha-Synuclein blood, Biomarkers cerebrospinal fluid, Biomarkers blood, Prion Proteins genetics, Prion Proteins cerebrospinal fluid, Prion Proteins blood, Prion Diseases genetics, Prion Diseases cerebrospinal fluid, Prion Diseases blood, Prion Diseases diagnosis
- Abstract
Objectives: To longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion., Methods: This single-center longitudinal cohort study has followed known carriers of PRNP pathogenic variants at risk for prion disease, individuals with a close relative who died of genetic prion disease but who have not undergone predictive genetic testing, and controls. All participants were asymptomatic at first visit and returned roughly annually. We determined PRNP genotypes, measured NfL and GFAP in plasma, and RT-QuIC, total PrP, NfL, T-tau, and beta-synuclein in CSF., Results: Among 41 carriers and 21 controls enrolled, 28 (68%) and 15 (71%) were female, and mean ages were 47.5 and 46.1. At baseline, all individuals were asymptomatic. We observed RT-QuIC seeding activity in the CSF of 3 asymptomatic E200K carriers who subsequently converted to symptomatic and died of prion disease. 1 P102L carrier remained RT-QuIC negative through symptom conversion. No other individuals developed symptoms. The prodromal window from detection of RT-QuIC positivity to disease onset was 1 year long in an E200K individual homozygous (V/V) at PRNP codon 129 and 2.5 and 3.1 years in 2 codon 129 heterozygotes (M/V). Changes in neurodegenerative and neuroinflammatory markers were variably observed prior to onset, with increases observed for plasma NfL in 4/4 converters, and plasma GFAP, CSF NfL, CSF T-tau, and CSF beta-synuclein each in 2/4 converters, although values relative to age and fold changes relative to individual baseline were not remarkable for any of these markers. CSF PrP was longitudinally stable with mean coefficient of variation 9.0% across all individuals over up to 6 years, including data from converting individuals at RT-QuIC-positive timepoints., Discussion: CSF prion seeding activity may represent the earliest detectable prodromal sign in E200K carriers. Neuronal damage and neuroinflammation markers show limited sensitivity in the prodromal phase. CSF PrP levels remain stable even in the presence of RT-QuIC seeding activity., Clinical Trials Registration: ClinicalTrials.gov NCT05124392 posted 2017-12-01, updated 2023-01-27.
- Published
- 2024
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11. Delivery of miR-15b-5p via magnetic nanoparticle-enhanced bone marrow mesenchymal stem cell-derived extracellular vesicles mitigates diabetic osteoporosis by targeting GFAP.
- Author
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Xu C, Wang Z, Liu Y, Duan K, and Guan J
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- Animals, Rats, Male, Cell Differentiation, Magnetite Nanoparticles, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Experimental genetics, Diabetes Complications metabolism, Diabetes Complications genetics, MicroRNAs genetics, MicroRNAs metabolism, Mesenchymal Stem Cells metabolism, Extracellular Vesicles metabolism, Extracellular Vesicles genetics, Osteoporosis metabolism, Osteoporosis genetics, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Rats, Sprague-Dawley, Osteoclasts metabolism
- Abstract
Diabetic osteoporosis (DO) presents significant clinical challenges. This study aimed to investigate the potential of magnetic nanoparticle-enhanced extracellular vesicles (GMNP
E -EVs) derived from bone marrow mesenchymal stem cells (BMSCs) to deliver miR-15b-5p, thereby targeting and downregulating glial fibrillary acidic protein (GFAP) expression in rat DO models. Data was sourced from DO-related RNA-seq datasets combined with GEO and GeneCards databases. Rat primary BMSCs, bone marrow-derived macrophages (BMMs), and osteoclasts were isolated and cultured. EVs were separated, and GMNPE targeting EVs were synthesized. Bioinformatic analysis revealed a high GFAP expression in DO-related RNA-seq and GSE26168 datasets for disease models. Experimental results confirmed elevated GFAP in rat DO bone tissues, promoting osteoclast differentiation. miR-15b-5p was identified as a GFAP inhibitor, but was significantly downregulated in DO and enriched in BMSC-derived EVs. In vitro experiments showed that GMNPE -EVs could transfer miR-15b-5p to osteoclasts, downregulating GFAP and inhibiting osteoclast differentiation. In vivo tests confirmed the therapeutic potential of this approach in alleviating rat DO. Collectively, GMNPE -EVs can effectively deliver miR-15b-5p to osteoclasts, downregulating GFAP expression, and hence, offering a therapeutic strategy for rat DO., (© 2024. The Author(s).)- Published
- 2024
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12. Characterization of Ocular Morphology in Col4a3-/- Mice as a Murine Model for Alport Syndrome.
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Wang Y, Zhu R, Zhao L, Wang F, Zhang Y, Liu S, Ding J, and Yang L
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- Animals, Mice, Retinal Pigment Epithelium pathology, Retinal Pigment Epithelium metabolism, Retinal Pigment Epithelium ultrastructure, Microscopy, Electron, Transmission, Mice, Inbred C57BL, Lens Capsule, Crystalline metabolism, Lens Capsule, Crystalline pathology, Lens Capsule, Crystalline ultrastructure, Epithelium, Corneal pathology, Epithelium, Corneal ultrastructure, Epithelium, Corneal metabolism, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Retina pathology, Retina metabolism, Retina ultrastructure, Autoantigens genetics, Autoantigens metabolism, Ependymoglial Cells pathology, Ependymoglial Cells metabolism, Ependymoglial Cells ultrastructure, Immunohistochemistry, Male, Nephritis, Hereditary pathology, Nephritis, Hereditary genetics, Nephritis, Hereditary metabolism, Collagen Type IV genetics, Collagen Type IV metabolism, Collagen Type IV deficiency, Disease Models, Animal, Basement Membrane metabolism, Basement Membrane pathology, Basement Membrane ultrastructure, Mice, Knockout
- Abstract
Purpose: The purpose of this study was to investigate the ocular morphological characteristics of Col4a3-/- mice as a model of Alport syndrome (AS) and the potential pathogenesis., Methods: The expression of collagen IV at 8, 12, and 21 weeks of age was evaluated by immunohistochemistry in wild-type (WT) and Col4a3-/- mice. Hematoxylin and eosin (H&E) staining and thickness measurements were performed to assess the thickness of anterior lens capsule and retina. Ultrastructure analysis of corneal epithelial basement membrane, anterior lens capsule, internal limiting membrane (ILM), and retinal pigment epithelium (RPE) basement membrane was performed using transmission electron microscopy. Finally, Müller cell activation was evaluated by glial fibrillary acidic protein (GFAP) expression., Results: Collagen IV was downregulated in the corneal epithelial basement membrane and ILM of Col4a3-/- mice. The hemidesmosomes of Col4a3-/- mice corneal epithelium became flat and less electron-dense than those of the WT group. Compared with those of the WT mice, the anterior lens capsules of Col4a3-/- mice were thinner. Abnormal structure was detected at the ILM Col4a3-/- mice, and the basal folds of the RPE basement membrane in Col4a3-/- mice were thicker and shorter. The retinas of Col4a3-/- mice were thinner than those of WT mice, especially within 1000 µm away from the optic nerve. GFAP expression enhanced in each age group of Col4a3-/- mice., Conclusions: Our results suggested that Col4a3-/- mice exhibit ocular anomalies similar to patients with AS. Additionally, Müller cells may be involved in AS retinal anomalies., Translational Relevance: This animal model could provide an opportunity to understand the underlying mechanisms of AS ocular disorders and to investigate potential new treatments.
- Published
- 2024
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13. Glial fibrillary acidic protein is pathologically modified in Alexander disease.
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Lin NH, Jian WS, Snider N, and Perng MD
- Subjects
- Humans, Animals, Mutation, Mice, Astrocytes metabolism, Astrocytes pathology, Brain metabolism, Brain pathology, Protein Processing, Post-Translational, Rats, Male, Female, Protein Aggregation, Pathological metabolism, Protein Aggregation, Pathological genetics, Protein Aggregation, Pathological pathology, Alexander Disease metabolism, Alexander Disease genetics, Alexander Disease pathology, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Ubiquitination
- Abstract
Here, we describe pathological events potentially involved in the disease pathogenesis of Alexander disease (AxD). This is a primary genetic disorder of astrocyte caused by dominant gain-of-function mutations in the gene coding for an intermediate filament protein glial fibrillary acidic protein (GFAP). Pathologically, this disease is characterized by the upregulation of GFAP and its accumulation as Rosenthal fibers. Although the genetic basis linking GFAP mutations with Alexander disease has been firmly established, the initiating events that promote GFAP accumulation and the role of Rosenthal fibers (RFs) in the disease process remain unknown. Here, we investigate the hypothesis that disease-associated mutations promote GFAP aggregation through aberrant posttranslational modifications. We found high molecular weight GFAP species in the RFs of AxD brains, indicating abnormal GFAP crosslinking as a prominent pathological feature of this disease. In vitro and cell-based studies demonstrate that cystine-generating mutations promote GFAP crosslinking by cysteine-dependent oxidation, resulting in defective GFAP assembly and decreased filament solubility. Moreover, we found GFAP was ubiquitinated in RFs of AxD patients and rodent models, supporting this modification as a critical factor linked to GFAP aggregation. Finally, we found that arginine could increase the solubility of aggregation-prone mutant GFAP by decreasing its ubiquitination and aggregation. Our study suggests a series of pathogenic events leading to AxD, involving interplay between GFAP aggregation and abnormal modifications by GFAP ubiquitination and oxidation. More important, our findings provide a basis for investigating new strategies to treat AxD by targeting abnormal GFAP modifications., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interests with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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14. The impact of astrocytic NF-κB on healthy and Alzheimer's disease brains.
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Jong Huat T, Camats-Perna J, Newcombe EA, Onraet T, Campbell D, Sucic JT, Martini A, Forner S, Mirzaei M, Poon W, LaFerla FM, and Medeiros R
- Subjects
- Animals, Female, Humans, Male, Mice, Amyloid beta-Peptides metabolism, Disease Models, Animal, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Signal Transduction, Alzheimer Disease metabolism, Alzheimer Disease pathology, Alzheimer Disease genetics, Astrocytes metabolism, Brain metabolism, Brain pathology, NF-kappa B metabolism
- Abstract
Astrocytes play a role in healthy cognitive function and Alzheimer's disease (AD). The transcriptional factor nuclear factor-κB (NF-κB) drives astrocyte diversity, but the mechanisms are not fully understood. By combining studies in human brains and animal models and selectively manipulating NF-κB function in astrocytes, we deepened the understanding of the role of astrocytic NF-κB in brain health and AD. In silico analysis of bulk and cell-specific transcriptomic data revealed the association of NF-κB and astrocytes in AD. Confocal studies validated the higher level of p50 NF-κB and phosphorylated-p65 NF-κB in glial fibrillary acidic protein (GFAP)
+ -astrocytes in AD versus non-AD subjects. In the healthy mouse brain, chronic activation of astrocytic NF-κB disturbed the proteomic milieu, causing a loss of mitochondrial-associated proteins and the rise of inflammatory-related proteins. Sustained NF-κB signaling also led to microglial reactivity, production of pro-inflammatory mediators, and buildup of senescence-related protein p16INK4A in neurons. However, in an AD mouse model, NF-κB inhibition accelerated β-amyloid and tau accumulation. Molecular biology studies revealed that astrocytic NF-κB activation drives the increase in GFAP and inflammatory proteins and aquaporin-4, a glymphatic system protein that assists in mitigating AD. Our investigation uncovered fundamental mechanisms by which NF-κB enables astrocytes' neuroprotective and neurotoxic responses in the brain., (© 2024. The Author(s).)- Published
- 2024
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15. Assessment of glial fibrillary acidic protein and anti-glial fibrillary acidic protein autoantibody concentrations and necrotising meningoencephalitis risk genotype in dogs with pug dog myelopathy.
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Rohdin C, Ljungvall I, Jäderlund KH, Svensson A, Lindblad-Toh K, and Häggström J
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- Animals, Dogs, Male, Female, Genotype, Genetic Predisposition to Disease, Dog Diseases genetics, Dog Diseases immunology, Meningoencephalitis veterinary, Meningoencephalitis genetics, Meningoencephalitis immunology, Autoantibodies blood, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein immunology, Spinal Cord Diseases veterinary, Spinal Cord Diseases genetics
- Abstract
Background: Pugs commonly present with thoracolumbar myelopathy, also known as pug dog myelopathy (PDM), which is clinically characterised by progressive signs involving the pelvic limbs, no apparent signs of pain and, often, incontinence. In addition to meningeal fibrosis and focal spinal cord destruction, histopathology has confirmed lymphohistiocytic infiltrates in the central nervous system (CNS) in a considerable number of pugs with PDM. Lymphohistiocytic CNS inflammation also characterises necrotising meningoencephalitis (NME) in pugs. This study aimed to investigate the potential contribution of an immunological aetiology to the development of PDM., Methods: The concentrations of glial fibrillary acidic protein (GFAP) in serum and CSF and of anti-GFAP autoantibodies in CSF were measured with an ELISA. In addition, a commercial test was used for genetic characterisation of the dog leukocyte antigen class II haplotype, which is associated with NME susceptibility., Results: This study included 87 dogs: 52 PDM pugs, 14 control pugs, four NME pugs and 17 dogs of breeds other than pugs that were investigated for neurological disease (neuro controls). Anti-GFAP autoantibodies were present in 15 of 19 (79%) of the PDM pugs tested versus six of 16 (38%) of the neuro controls tested (p = 0.018). All 18 PDM pugs evaluated had detectable CSF GFAP. Serum GFAP was detected in two of three (67%) of the NME pugs and in two of 11 (18%) of the control pugs but not in any of the 40 tested PDM pugs. Male pugs heterozygous for the NME risk haplotype had an earlier onset of clinical signs (70 months) compared to male pugs without the risk haplotype (78 months) (p = 0.036)., Limitations: The study was limited by the lack of healthy dogs of breeds other than pugs and the small numbers of control pugs and pugs with NME., Conclusions: The high proportion of PDM pugs with anti-GFAP autoantibodies and high CSF GFAP concentrations provide support for a potential immunological contribution to the development of PDM., (© 2024 The Authors. Veterinary Record published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)
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- 2024
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16. Kisspeptin signaling in astrocytes modulates the reproductive axis.
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Torres E, Pellegrino G, Granados-Rodríguez M, Fuentes-Fayos AC, Velasco I, Coutteau-Robles A, Legrand A, Shanabrough M, Perdices-Lopez C, Leon S, Yeo SH, Manchishi SM, Sánchez-Tapia MJ, Navarro VM, Pineda R, Roa J, Naftolin F, Argente J, Luque RM, Chowen JA, Horvath TL, Prevot V, Sharif A, Colledge WH, Tena-Sempere M, and Romero-Ruiz A
- Subjects
- Animals, Mice, Humans, Rats, Female, Male, Hypothalamus metabolism, Neurons metabolism, Dinoprostone metabolism, S100 Calcium Binding Protein beta Subunit metabolism, S100 Calcium Binding Protein beta Subunit genetics, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Reproduction, Kisspeptins metabolism, Kisspeptins genetics, Astrocytes metabolism, Receptors, Kisspeptin-1 metabolism, Receptors, Kisspeptin-1 genetics, Signal Transduction, Gonadotropin-Releasing Hormone metabolism, Gonadotropin-Releasing Hormone genetics, Mice, Knockout
- Abstract
Reproduction is safeguarded by multiple, often cooperative, regulatory networks. Kisspeptin signaling, via KISS1R, plays a fundamental role in reproductive control, primarily by regulation of hypothalamic GnRH neurons. We disclose herein a pathway for direct kisspeptin actions in astrocytes that contributes to central reproductive modulation. Protein-protein interaction and ontology analyses of hypothalamic proteomic profiles after kisspeptin stimulation revealed that glial/astrocyte markers are regulated by kisspeptin in mice. This glial-kisspeptin pathway was validated by the demonstrated expression of Kiss1r in mouse astrocytes in vivo and astrocyte cultures from humans, rats, and mice, where kisspeptin activated canonical intracellular signaling-pathways. Cellular coexpression of Kiss1r with the astrocyte markers GFAP and S100-β occurred in different brain regions, with higher percentage in Kiss1- and GnRH-enriched areas. Conditional ablation of Kiss1r in GFAP-positive cells in the G-KiR-KO mouse altered gene expression of key factors in PGE2 synthesis in astrocytes and perturbed astrocyte-GnRH neuronal appositions, as well as LH responses to kisspeptin and LH pulsatility, as surrogate marker of GnRH secretion. G-KiR-KO mice also displayed changes in reproductive responses to metabolic stress induced by high-fat diet, affecting female pubertal onset, estrous cyclicity, and LH-secretory profiles. Our data unveil a nonneuronal pathway for kisspeptin actions in astrocytes, which cooperates in fine-tuning the reproductive axis and its responses to metabolic stress.
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- 2024
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17. Evaluation of safety and early efficacy of AAV gene therapy in mouse models of vanishing white matter disease.
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Herstine JA, Chang PK, Chornyy S, Stevenson TJ, Sunshine AC, Nokhrina K, Rediger J, Wentz J, Vetter TA, Scholl E, Holaway C, Pyne NK, Bratasz A, Yeoh S, Flanigan KM, Bonkowsky JL, and Bradbury AM
- Subjects
- Animals, Mice, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Humans, Dependovirus genetics, Disease Models, Animal, Leukoencephalopathies therapy, Leukoencephalopathies genetics, Leukoencephalopathies etiology, Genetic Therapy methods, Genetic Vectors genetics, Genetic Vectors administration & dosage, Astrocytes metabolism, Astrocytes pathology, Eukaryotic Initiation Factor-2B genetics, Eukaryotic Initiation Factor-2B metabolism
- Abstract
Leukoencephalopathy with vanishing white matter (VWM) is a progressive incurable white matter disease that most commonly occurs in childhood and presents with ataxia, spasticity, neurological degeneration, seizures, and premature death. A distinctive feature is episodes of rapid neurological deterioration provoked by stressors such as infection, seizures, or trauma. VWM is caused by autosomal recessive mutations in one of five genes that encode the eukaryotic initiation factor 2B complex, which is necessary for protein translation and regulation of the integrated stress response. The majority of mutations are in EIF2B5. Astrocytic dysfunction is central to pathophysiology, thereby constituting a potential therapeutic target. Herein we characterize two VWM murine models and investigate astrocyte-targeted adeno-associated virus serotype 9 (AAV9)-mediated EIF2B5 gene supplementation therapy as a therapeutic option for VWM. Our results demonstrate significant rescue in body weight, motor function, gait normalization, life extension, and finally, evidence that gene supplementation attenuates demyelination. Last, the greatest rescue results from a vector using a modified glial fibrillary acidic protein (GFAP) promoter-AAV9-gfaABC(1)D-EIF2B5-thereby supporting that astrocytic targeting is critical for disease correction. In conclusion, we demonstrate safety and early efficacy through treatment with a translatable astrocyte-targeted gene supplementation therapy for a disease that has no cure., Competing Interests: Declaration of interests J.L.B. is on the board of wFluidx, Inc., owns stock in Orchard Therapeutics, and has consulted for Bluebird bio, Calico Life Sciences, Denali Therapeutics, Enzyvant, and Neurogene. A.M.B. is a beneficiary of a licensing agreement with Axovant Gene Therapies (royalties) and Neurogene (royalties) and has received income from Neurogene (consulting and honorarium). A.M.B., K.M.F., J.L.B., N.K.P., and J.A.H. are inventors on a provisional patent: Materials and Methods for the Treatment of EIF2B5 Mutations and Diseases Resulting Therefrom. Provisional Patent 63/316,241., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2024
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18. Cytokine Levels in Experimental Branch Retinal Vein Occlusion Treated With Either Bevacizumab or Triamcinolone Acetonide.
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McAllister IL, Vijayasekaran S, McLenachan S, Bhikoo R, Chen FK, Zhang D, Kanagalingam E, and Yu DY
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- Animals, Swine, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor A genetics, RNA, Messenger metabolism, RNA, Messenger genetics, Glucocorticoids pharmacology, Glucocorticoids therapeutic use, Gene Expression Regulation drug effects, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Potassium Channels, Inwardly Rectifying, Bevacizumab pharmacology, Bevacizumab therapeutic use, Triamcinolone Acetonide pharmacology, Triamcinolone Acetonide administration & dosage, Triamcinolone Acetonide therapeutic use, Retinal Vein Occlusion drug therapy, Retinal Vein Occlusion metabolism, Disease Models, Animal, Angiogenesis Inhibitors pharmacology, Angiogenesis Inhibitors therapeutic use, Angiogenesis Inhibitors administration & dosage, Cytokines metabolism, Cytokines genetics, Intravitreal Injections
- Abstract
Purpose: To compare gene expression changes following branch retinal vein occlusion (BRVO) in the pig with and without bevacizumab (BEV) and triamcinolone acetonide (TA)., Methods: Photothrombotic BRVOs were created in both eyes of four groups of nine pigs (2, 6, 10, and 20 days). In each group, six pigs received intravitreal injections of BEV in one eye and TA in the fellow eye, with three pigs serving as untreated BRVO controls. Three untreated pigs served as healthy controls. Expression of mRNA of vascular endothelial growth factor (VEGF), glial fibrillary acidic protein (GFAP), dystrophin (DMD), potassium inwardly rectifying channel subfamily J member 10 protein (Kir4.1, KCNJ10), aquaporin-4 (AQP4), stromal cell-derived factor-1α (CXCL12), interleukin-6 (IL6), interleukin-8 (IL8), monocyte chemoattractant protein-1 (CCL2), intercellular adhesion molecule 1 (ICAM1), and heat shock factor 1 (HSF1) were analyzed by quantitative reverse-transcription polymerase chain reaction. Retinal VEGF protein levels were characterized by immunohistochemistry., Results: In untreated eyes, BRVO significantly increased expression of GFAP, IL8, CCL2, ICAM1, HSF1, and AQP4. Expression of VEGF, KCNJ10, and CXCL12 was significantly reduced by 6 days post-BRVO, with expression recovering to healthy control levels by day 20. Treatment with BEV or TA significantly increased VEGF, DMD, and IL6 expression compared with untreated BRVO eyes and suppressed BRVO-induced CCL2 and AQP4 upregulation, as well as recovery of KCNJ10 expression, at 10 to 20 days post-BRVO., Conclusions: Inflammation and cellular osmohomeostasis rather than VEGF suppression appear to play important roles in BRVO-induced retinal neurodegeneration, enhanced in both BEV- and TA-treated retinas., Translational Relevance: Inner retinal neurodegeneration seen in this acute model of BRVO appears to be mediated by inflammation and alterations in osmohomeostasis rather than VEGF inhibition, which may have implications for more specific treatment modalities in the acute phase of BRVO.
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- 2024
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19. Evaluation of histological and ultrastructural changes provoked by prenatal tramadol on postnatal cortical cerebellar neuronal development in rats: possible implication of Ki67, GFAP and MicroRNA-7/P53 signalling trajectories.
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Abdelmoez WA
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- Animals, Pregnancy, Female, Rats, Cerebellum drug effects, Cerebellum ultrastructure, Cerebellum metabolism, Neurons drug effects, Neurons metabolism, Neurons ultrastructure, Apoptosis drug effects, Rats, Wistar, Animals, Newborn, Tramadol pharmacology, Tramadol adverse effects, MicroRNAs genetics, MicroRNAs metabolism, Signal Transduction drug effects, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Prenatal Exposure Delayed Effects, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Ki-67 Antigen metabolism, Ki-67 Antigen genetics
- Abstract
Tramadol is a novel centrally acting analgesic. Despite, its implementation during pregnancy may impair neuronal survival and synaptic development in neonatal cerebella. The current investigation assessed the histological and ultrastructural alterations in postnatal cortical cerebellar neuronal development induced by prenatal tramadol. 30 offsprings were divided to control group I: fifteen pups born to mothers given saline from D10 till D21 of gestation. Tramadol-treated group II: fifteen pups born to mothers received tramadol HCL (50 mg/kg/day) from D10 till D21 of gestation. Pups were categorized into three subgroups (a, b, and c) and offered for sacrifice on the seventh, fourteenth and twenty-first post-natal days. Light microscopic examination revealed the overcrowding and signs of red degeneration affecting purkinje cell layer. Neurodegenerative signs of both purkinje and granule cell neurons were also confirmed by TEM in form of chromatin condensation, dilated Golgi channels, disrupted endoplasmic reticulum, marked infolding of the nuclear envelope and decrease in granule cell precursors. In addition, the astrocytic processes and terminal nerve axons appeared with different degrees of demyelination and decreased number of oligodendrocytes and degenerated mitochondria. Furthermore, group II exhibited an increase in P53 immune expression. The area percentage of apoptotic cells detected by TUNEL assay was significantly increased. Besides to the significant decrease of Ki67 immunoreactivity in the stem neuronal cell progenitors. Quantitative PCR results showed a significant decline in micro RNA7 gene expression in tramadol treated groups resulting in affection of multiple target genes in P53 signaling pathways, improper cortical size and defect in neuronal development., (© 2024. The Author(s).)
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- 2024
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20. High-Caloric Diets in Adolescence Impair Specific GABAergic Subpopulations, Neurogenesis, and Alter Astrocyte Morphology.
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Mota B, Brás AR, Araújo-Andrade L, Silva A, Pereira PA, Madeira MD, and Cardoso A
- Subjects
- Animals, Rats, Male, GABAergic Neurons metabolism, Brain-Derived Neurotrophic Factor metabolism, Brain-Derived Neurotrophic Factor genetics, Neuropeptide Y metabolism, Neuropeptide Y genetics, Rats, Wistar, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Parvalbumins metabolism, Astrocytes metabolism, Reelin Protein metabolism, Neurogenesis, Hippocampus metabolism, Cyclin-Dependent Kinase 5 metabolism, Cyclin-Dependent Kinase 5 genetics
- Abstract
We compared the effects of two different high-caloric diets administered to 4-week-old rats for 12 weeks: a diet rich in sugar (30% sucrose) and a cafeteria diet rich in sugar and high-fat foods. We focused on the hippocampus, particularly on the gamma-aminobutyric acid (GABA)ergic system, including the Ca
2+ -binding proteins parvalbumin (PV), calretinin (CR), calbindin (CB), and the neuropeptides somatostatin (SST) and neuropeptide Y (NPY). We also analyzed the density of cholinergic varicosities, brain-derived neurotrophic factor ( BDNF ), reelin ( RELN ), and cyclin-dependent kinase-5 ( CDK-5 ) mRNA levels, and glial fibrillary acidic protein (GFAP) expression. The cafeteria diet reduced PV-positive neurons in the granular layer, hilus, and CA1, as well as NPY-positive neurons in the hilus, without altering other GABAergic populations or overall GABA levels. The high-sugar diet induced a decrease in the number of PV-positive cells in CA3 and an increase in CB-positive cells in the hilus and CA1. No alterations were observed in the cholinergic varicosities. The cafeteria diet also reduced the relative mRNA expression of RELN without significant changes in BDNF and CDK5 levels. The cafeteria diet increased the number but reduced the length of the astrocyte processes. These data highlight the significance of determining the mechanisms mediating the observed effects of these diets and imply that the cognitive impairments previously found might be related to both the neuroinflammation process and the reduction in PV, NPY, and RELN expression in the hippocampal formation.- Published
- 2024
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21. Astrogliosis in the GFAP-Cre ERT2 :Rosa26 iDTR Mouse Model Does Not Exacerbate Retinal Microglia Activation or Müller Cell Gliosis under Hypoxic Conditions.
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Rorex C, Cardona SM, Church KA, Rodriguez D, Vanegas D, Saldivar R, Faz B, and Cardona AE
- Subjects
- Animals, Mice, Astrocytes metabolism, Astrocytes pathology, Astrocytes drug effects, Cytokines metabolism, Diabetic Retinopathy metabolism, Diabetic Retinopathy pathology, Diphtheria Toxin, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein metabolism, Hypoxia metabolism, Hypoxia pathology, Retina metabolism, Retina pathology, Retina drug effects, Vimentin metabolism, Vimentin genetics, Disease Models, Animal, Ependymoglial Cells metabolism, Ependymoglial Cells pathology, Ependymoglial Cells drug effects, Gliosis pathology, Gliosis metabolism, Gliosis chemically induced, Mice, Transgenic, Microglia metabolism, Microglia pathology, Microglia drug effects
- Abstract
Diabetic retinopathy (DR) affects over 140 million people globally. The mechanisms that lead to blindness are still enigmatic but there is evidence that sustained inflammation and hypoxia contribute to vascular damage. Despite efforts to understand the role of inflammation and microglia in DR's pathology, the contribution of astrocytes to hypoxic responses is less clear. To investigate the role of astrocytes in hypoxia-induced retinopathy, we utilized a 7-day systemic hypoxia model using the GFAP-Cre
ERT2 :Rosa26iDTR transgenic mouse line. This allows for the induction of inflammatory reactive astrogliosis following tamoxifen and diphtheria toxin administration. We hypothesize that DTx-induced astrogliosis is neuroprotective during hypoxia-induced retinopathy. Glial, neuronal, and vascular responses were quantified using immunostaining, with antibodies against GFAP, vimentin, IBA-1, NeuN, fibrinogen, and CD31. Cytokine responses were measured in both the brain and serum. We report that while both DTx and hypoxia induced a phenotype of reduced microglia morphological activation, DTx, but not hypoxia, induced an increase in the Müller glia marker vimentin. We did not observe that the combination of DTx and hypoxic treatments exacerbated the signs of reactive glial cells, nor did we observe a significant change in the expression immunomodulatory mediators IL-1β, IL2, IL-4, IL-5, IL-6, IL-10, IL-18, CCL17, TGF-β1, GM-CSF, TNF-α, and IFN-γ. Overall, our results suggest that, in this hypoxia model, reactive astrogliosis does not alter the inflammatory responses or cause vascular damage in the retina.- Published
- 2024
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22. [Expression changes of RNA m6A regulators in mouse cerebellum affected by hypobaric hypoxia stimulation].
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Xiao LF, Ma CH, Zhao SL, Li Q, Liu CY, Niu YM, and Tong WM
- Subjects
- Animals, Mice, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Astrocytes metabolism, Down-Regulation, Methylation, Adenosine metabolism, Adenosine analogs & derivatives, Nervous System Malformations metabolism, Nervous System Malformations genetics, Cerebellum metabolism, Mice, Inbred C57BL, Hypoxia metabolism, Nerve Tissue Proteins metabolism, Nerve Tissue Proteins genetics, Purkinje Cells metabolism, Purkinje Cells pathology, Calbindins metabolism, Calbindins genetics, Methyltransferases metabolism, Methyltransferases genetics, DNA-Binding Proteins
- Abstract
Objective: To investigate the role of RNA m6A methylation in mediating cerebellar dysplasia through analyzing the phenotypes of the mouse cerebella and the expression of several key m6A regulators upon hypobaric hypoxia treatment. Methods: Five-day old C57/BL6 mice were exposed to hypobaric hypoxia for 9 days. The status of mouse cerebellar development was analyzed by comparing the body weights, brain weights and histological features. Immunostaining of cell-type-specific markers was performed to analyze the cerebellar morphology. Real-time PCR, Western blot and immunohistochemical staining were performed to detect the expression of key m6A regulators in the mouse cerebella. Results: Compared with the control, the body weights, brain weights and cerebellar volumes of hypobaric hypoxic mice were significantly reduced ( P< 0.01). The expression of specific markers in different cells, including NeuN (mature neuron), Calbindin-D28K (Purkinje cell) and GFAP (astrocyte), was decreased in hypobaric hypoxic mouse cerebella ( P< 0.01), accompanied with disorganized cellular structure. The expression of methyltransferase METTL3 was significantly down-regulated in the cerebella of hypobaric hypoxic mice ( P< 0.05). Conclusions: Hypobaric hypoxia stimulation causes mouse cerebellar dysplasia, with structural abnormalities in mature granular neurons, Purkinje cells and astrocytes. Expression of METTL3 is decreased in hypobaric hypoxic mice cerebellum compared with that of normobaric normoxic mice, suggesting that its mediated RNA m6A methylation may play an important role in hypobaric hypoxia-induced mouse cerebellar dysplasia.
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- 2024
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23. [Pilocytic astrocytoma with KRAS gene mutation: a clinicopathological analysis of two cases].
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Yu TP, Zhang MX, Zhang JY, Gong J, Zhou Q, and Chen N
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- Humans, Female, Adolescent, Adult, Retrospective Studies, DNA Methylation, Proto-Oncogene Proteins B-raf genetics, In Situ Hybridization, Fluorescence, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Astrocytoma genetics, Astrocytoma pathology, Astrocytoma metabolism, Proto-Oncogene Proteins p21(ras) genetics, Mutation, Brain Neoplasms genetics, Brain Neoplasms pathology, Brain Neoplasms metabolism
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- 2024
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24. Implication of system x c - in neuroinflammation during the onset and maintenance of neuropathic pain.
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Beckers P, Belo Do Nascimento I, Charlier M, Desmet N, Massie A, and Hermans E
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- Animals, Female, Mice, Biomarkers metabolism, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein metabolism, Gliosis complications, Gliosis drug therapy, Gliosis physiopathology, Glutamic Acid metabolism, Hyperalgesia drug therapy, Mice, Transgenic, Microglia drug effects, Microglia metabolism, Microglia pathology, Phenotype, Reproducibility of Results, RNA, Messenger drug effects, RNA, Messenger genetics, RNA, Messenger metabolism, Sciatic Neuropathy complications, Sciatic Neuropathy physiopathology, Spinal Cord drug effects, Spinal Cord pathology, Spinal Cord physiopathology, Sulfasalazine pharmacology, Sulfasalazine therapeutic use, Amino Acid Transport System y+ antagonists & inhibitors, Amino Acid Transport System y+ deficiency, Amino Acid Transport System y+ genetics, Amino Acid Transport System y+ metabolism, Neuralgia complications, Neuralgia drug therapy, Neuralgia physiopathology, Neuralgia prevention & control, Neuroinflammatory Diseases complications, Neuroinflammatory Diseases drug therapy, Neuroinflammatory Diseases physiopathology, Neuroinflammatory Diseases prevention & control
- Abstract
Background: Despite the high prevalence of neuropathic pain, treating this neurological disease remains challenging, given the limited efficacy and numerous side effects associated with current therapies. The complexity in patient management is largely attributed to an incomplete understanding of the underlying pathological mechanisms. Central sensitization, that refers to the adaptation of the central nervous system to persistent inflammation and heightened excitatory transmission within pain pathways, stands as a significant contributor to persistent pain. Considering the role of the cystine/glutamate exchanger (also designated as system x
c - ) in modulating glutamate transmission and in supporting neuroinflammatory responses, we investigated the contribution of this exchanger in the development of neuropathic pain., Methods: We examined the implication of system xc - by evaluating changes in the expression/activity of this exchanger in the dorsal spinal cord of mice after unilateral partial sciatic nerve ligation. In this surgical model of neuropathic pain, we also examined the consequence of the genetic suppression of system xc - (using mice lacking the system xc - specific subunit xCT) or its pharmacological manipulation (using the pharmacological inhibitor sulfasalazine) on the pain-associated behavioral responses. Finally, we assessed the glial activation and the inflammatory response in the spinal cord by measuring mRNA and protein levels of GFAP and selected M1 and M2 microglial markers., Results: The sciatic nerve lesion was found to upregulate system xc - at the spinal level. The genetic deletion of xCT attenuated both the amplitude and the duration of the pain sensitization after nerve surgery, as evidenced by reduced responses to mechanical and thermal stimuli, and this was accompanied by reduced glial activation. Consistently, pharmacological inhibition of system xc - had an analgesic effect in lesioned mice., Conclusion: Together, these observations provide evidence for a role of system xc - in the biochemical processes underlying central sensitization. We propose that the reduced hypersensitivity observed in the transgenic mice lacking xCT or in sulfasalazine-treated mice is mediated by a reduced gliosis in the lumbar spinal cord and/or a shift in microglial M1/M2 polarization towards an anti-inflammatory phenotype in the absence of system xc - . These findings suggest that drugs targeting system xc - could contribute to prevent or reduce neuropathic pain., (© 2024. The Author(s).)- Published
- 2024
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25. Observing astrocyte polarization in brains from mouse chronically infected with Toxoplasma gondii.
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Yao Y, Yuan Y, Sheng S, Li Y, Tang X, and Gu H
- Subjects
- Animals, Mice, Disease Models, Animal, Female, Chronic Disease, Cell Polarity, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Toxoplasmosis metabolism, Toxoplasmosis parasitology, Toxoplasmosis pathology, Tumor Necrosis Factor-alpha metabolism, Toxoplasmosis, Cerebral parasitology, Toxoplasmosis, Cerebral pathology, Toxoplasmosis, Cerebral metabolism, Astrocytes metabolism, Astrocytes parasitology, Astrocytes pathology, Toxoplasma pathogenicity, Toxoplasma physiology, Brain parasitology, Brain metabolism, Brain pathology
- Abstract
Toxoplasma gondii (T. gondii) is a protozoan parasite that infects approximately one-third of the global human population, often leading to chronic infection. While acute T. gondii infection can cause neural damage in the central nervous system and result in toxoplasmic encephalitis, the consequences of T. gondii chronic infection (TCI) are generally asymptomatic. However, emerging evidence suggests that TCI may be linked to behavioral changes or mental disorders in hosts. Astrocyte polarization, particularly the A1 subtype associated with neuronal apoptosis, has been identified in various neurodegenerative diseases. Nevertheless, the role of astrocyte polarization in TCI still needs to be better understood. This study aimed to establish a mouse model of chronic TCI and examine the transcription and expression levels of glial fibrillary acidic protein (GFAP), C3, C1q, IL-1α, and TNF-α in the brain tissues of the mice. Quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay, and Western blotting were employed to assess these levels. Additionally, the expression level of the A1 astrocyte-specific marker C3 was evaluated using indirect fluorescent assay (IFA). In mice with TCI, the transcriptional and expression levels of the inflammatory factors C1q, IL-1α, and TNF-α followed an up-down-up pattern, although they remained elevated compared to the control group. These findings suggest a potential association between astrocyte polarization towards the A1 subtype and synchronized changes in these three inflammatory mediators. Furthermore, immunofluorescence assay (IFA) revealed a significant increase in the A1 astrocytes (GFAP
+ C3+ ) proportion in TCI mice. This study provides evidence that TCI can induce astrocyte polarization, a biological process that may be influenced by changes in the levels of three inflammatory factors: C1q, IL-1α, and TNF-α. Additionally, the release of neurotoxic substances by A1 astrocytes may be associated with the development of TCI., (© 2024. The Author(s).)- Published
- 2024
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26. Comparative Morphological and Molecular Genetic Characteristics of Cell and Tissue Strains of Experimental Rat Glioma 10-17-2 (Astrid-17).
- Author
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Alekseeva AI, Kudelkina VV, Khalansky AS, Sentyabreva AV, Miroshnichenko EA, Gulyaev MV, Rakitina KA, and Kosyreva AM
- Subjects
- Animals, Rats, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Ki-67 Antigen metabolism, Ki-67 Antigen genetics, Male, Astrocytoma genetics, Astrocytoma pathology, Astrocytoma metabolism, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Brain pathology, Brain metabolism, Brain Neoplasms genetics, Brain Neoplasms pathology, Brain Neoplasms metabolism, Glioma genetics, Glioma pathology, Glioma metabolism, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein metabolism, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism
- Abstract
In order to obtain models of gliomas of varying degrees of malignancy, we performed morphological and molecular genetic study of a tissue strain of glioma 10-17-2 (Astrid-17) obtained by intracranial passaging of tumor fragments of chemically induced rat brain tumor, and a cell strain isolated from it. More or less pronounced changes in the expression levels of Mki67, Trp53, Vegfa, and Gfap genes in the tissue and cell strain of glioma 10-17-2 (Astrid-17) compared with intact brain tissue were shown. The tissue model of glioma 10-17-2 (Astrid-17) according to the studied characteristics shows features of grade 3-4 astrocytoma and the cellular model - grade 2-3 astrocytoma., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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27. Alexander disease with a novel GFAP insertion-deletion mutation mimicking progressive supranuclear palsy.
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Shiina A, Ishikawa D, Ishizawa K, Kasahara H, Fujita Y, Mizuta I, Yoshida T, and Ikeda Y
- Subjects
- Humans, Female, Aged, Diagnosis, Differential, Tomography, Emission-Computed, Single-Photon, Brain diagnostic imaging, Brain pathology, Mutagenesis, Insertional genetics, Alexander Disease genetics, Alexander Disease diagnostic imaging, Alexander Disease diagnosis, Supranuclear Palsy, Progressive genetics, Supranuclear Palsy, Progressive diagnostic imaging, Glial Fibrillary Acidic Protein genetics, Magnetic Resonance Imaging
- Abstract
This report presents a case of Alexander disease showing clinical characteristics mimicking progressive supranuclear palsy (PSP). A 67-year-old woman complaining of motor disturbance exhibited severe atrophy of medulla, spinal cord, and midbrain tegmentum, as well as periventricular hyperintensity on cerebral MRI. Genetic analysis identified a novel in-frame deletion/insertion mutation in the exon 3 of the GFAP gene. Interestingly, neurological findings and decreased striatal uptake in dopamine transporter SPECT were suggestive of PSP. A novel GFAP gene mutation found in the present case may cause the unique clinical phenotype, which should be differentiated from PSP., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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28. Structural flexibility and heterogeneity of recombinant human glial fibrillary acidic protein (GFAP).
- Author
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Gogishvili D, Illes-Toth E, Harris MJ, Hopley C, Teunissen CE, and Abeln S
- Subjects
- Humans, Protein Conformation, Reproducibility of Results, Recombinant Proteins, Deuterium Exchange Measurement methods, Glial Fibrillary Acidic Protein chemistry, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein physiology, Phosphates
- Abstract
Glial fibrillary acidic protein (GFAP) is a promising biomarker for brain and spinal cord disorders. Recent studies have highlighted the differences in the reliability of GFAP measurements in different biological matrices. The reason for these discrepancies is poorly understood as our knowledge of the protein's 3-dimensional conformation, proteoforms, and aggregation remains limited. Here, we investigate the structural properties of GFAP under different conditions. For this, we characterized recombinant GFAP proteins from various suppliers and applied hydrogen-deuterium exchange mass spectrometry (HDX-MS) to provide a snapshot of the conformational dynamics of GFAP in artificial cerebrospinal fluid (aCSF) compared to the phosphate buffer. Our findings indicate that recombinant GFAP exists in various conformational species. Furthermore, we show that GFAP dimers remained intact under denaturing conditions. HDX-MS experiments show an overall decrease in H-bonding and an increase in solvent accessibility of GFAP in aCSF compared to the phosphate buffer, with clear indications of mixed EX2 and EX1 kinetics. To understand possible structural interface regions and the evolutionary conservation profiles, we combined HDX-MS results with the predicted GFAP-dimer structure by AlphaFold-Multimer. We found that deprotected regions with high structural flexibility in aCSF overlap with predicted conserved dimeric 1B and 2B domain interfaces. Structural property predictions combined with the HDX data show an overall deprotection and signatures of aggregation in aCSF. We anticipate that the outcomes of this research will contribute to a deeper understanding of the structural flexibility of GFAP and ultimately shed light on its behavior in different biological matrices., (© 2023 The Authors. Proteins: Structure, Function, and Bioinformatics published by Wiley Periodicals LLC.)
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- 2024
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29. Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy Is Associated with HLA-A*3303 and HLA-DPB1*0501.
- Author
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Shu Y, Huang R, Li Q, Lu Y, Yin J, Li H, Lan Z, Zheng X, Ye J, Long Y, Wang Z, Xiao L, Zhou Q, Liu X, Fu Y, Chen H, Chen J, Zhou Y, Zhou J, Zhang L, Zhou J, Jiang Y, Peng F, Lu Z, Petersen F, Qiu W, and Yu X
- Subjects
- Humans, Male, Female, Middle Aged, Adult, Aged, Glial Fibrillary Acidic Protein genetics, HLA-DP beta-Chains genetics, HLA-A Antigens genetics, Astrocytes metabolism, Astrocytes pathology
- Abstract
We determined the genetic association between specific human leucocyte antigen (HLA) loci and autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. Our results showed that autoimmune GFAP astrocytopathy was associated with HLA-A*3303 (odds ratio [OR] = 2.02, 95% confidence interval [CI] = 1.32-3.06, p = 0.00072, p
adj. = 0.046) and HLA-DBP1*0501 (OR = 0.51, 95% CI = 0.36-0.71, p = 0.000048, padj. = 0.0062). Moreover, HLA-A*3303 carriers with the disease had a longer hospital stay (p = 0.0005) than non-carriers. This study for the first time provides evidence for a role of genetic factor in the development of autoimmune GFAP astrocytopathy. ANN NEUROL 2024;95:901-906., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)- Published
- 2024
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30. Lipid peroxidation-induced ferroptosis as a therapeutic target for mitigating neuronal injury and inflammation in sepsis-associated encephalopathy: insights into the hippocampal PEBP-1/15-LOX/GPX4 pathway.
- Author
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Wang H, Xu L, Tang X, Jiang Z, and Feng X
- Subjects
- Animals, Humans, Mice, Male, Female, Neurons metabolism, Neurons drug effects, Neurons pathology, Coenzyme A Ligases metabolism, Coenzyme A Ligases genetics, Coenzyme A Ligases antagonists & inhibitors, Inflammation metabolism, Inflammation pathology, Inflammation drug therapy, Amino Acid Transport System y+ metabolism, Amino Acid Transport System y+ genetics, S100 Calcium Binding Protein beta Subunit metabolism, S100 Calcium Binding Protein beta Subunit genetics, Disease Models, Animal, Child, Preschool, Leukocytes, Mononuclear metabolism, Leukocytes, Mononuclear drug effects, Signal Transduction drug effects, Child, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Malondialdehyde metabolism, Sepsis complications, Sepsis metabolism, Sepsis drug therapy, Infant, Ferroptosis drug effects, Hippocampus metabolism, Hippocampus drug effects, Hippocampus pathology, Sepsis-Associated Encephalopathy drug therapy, Sepsis-Associated Encephalopathy metabolism, Sepsis-Associated Encephalopathy pathology, Phospholipid Hydroperoxide Glutathione Peroxidase metabolism, Phospholipid Hydroperoxide Glutathione Peroxidase genetics, Lipid Peroxidation drug effects, Phosphatidylethanolamine Binding Protein metabolism, Phosphatidylethanolamine Binding Protein genetics
- Abstract
Background: Sepsis-associated encephalopathy (SAE) refers to the widespread impairment of brain function caused by noncentral nervous system infection mediated by sepsis. Lipid peroxidation-induced ferroptosis contributes to the occurrence and course of SAE. This study aimed to investigate the relationship between neuronal injury and lipid peroxidation-induced ferroptosis in SAE., Methods: Baseline data were collected from pediatric patients upon admission, and the expression levels of various markers related to lipid peroxidation and ferroptosis were monitored in the serum and peripheral blood mononuclear cells (PBMCs) of patients with SAE as well as SAE model mice. The hippocampal phosphatidylethanolamine-binding protein (PEBP)-1/15-lysine oxidase (LOX)/ glutathione peroxidase 4 (GPX4) pathway was assessed for its role on the inhibitory effect of ferroptosis in SAE treatment., Results: The results showed elevated levels of S100 calcium-binding protein beta (S-100β), glial fibrillary acidic protein, and malondialdehyde in the serum of SAE patients, while superoxide dismutase levels were reduced. Furthermore, analysis of PBMCs revealed increased transcription levels of PEBP1, LOX, and long-chain fatty acyl-CoA synthetase family member 4 (ACSL4) in SAE patients, while the transcription levels of GPX4 and cystine/glutamate transporter xCT (SLC7A11) were decreased. In comparison to the control group, the SAE mice exhibited increased expression of S-100β and neuron-specific enolase (NSE) in the hippocampus, whereas the expression of S-100β and NSE were reduced in deferoxamine (DFO) mice. Additionally, iron accumulation was observed in the hippocampus of SAE mice, while the iron ion levels were reduced in the DFO mice. Inhibition of ferroptosis alleviated the mitochondrial damage (as assessed by transmission electron microscopy, hippocampal mitochondrial ATP detection, and the JC-1 polymer-to-monomer ratio in the hippocampus) and the oxidative stress response induced by SAE as well as attenuated neuroinflammatory reactions. Further investigations revealed that the mechanism underlying the inhibitory effect of ferroptosis in SAE treatment is associated with the hippocampal PEBP-1/15-LOX/GPX4 pathway., Conclusion: These results offer potential therapeutic targets for the management of neuronal injury in SAE and valuable insights into the potential mechanisms of ferroptosis in neurological disorders., (© 2024. The Author(s).)
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- 2024
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31. [Repair effect of different doses of human umbilical cord mesenchymal stem cells on white matter injury in neonatal rats].
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Zhang J, Li MX, Wang C, Xu QQ, Zhang SJ, and Zhu YP
- Subjects
- Animals, Rats, Humans, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein analysis, Mesenchymal Stem Cells, Myelin Basic Protein genetics, Myelin Basic Protein analysis, Myelin Basic Protein metabolism, Male, Apoptosis, Female, RNA, Messenger analysis, RNA, Messenger metabolism, Rats, Sprague-Dawley, Animals, Newborn, Umbilical Cord cytology, Mesenchymal Stem Cell Transplantation, White Matter pathology, White Matter metabolism
- Abstract
Objectives: To compare the repair effects of different doses of human umbilical cord mesenchymal stem cells (hUC-MSCs) on white matter injury (WMI) in neonatal rats., Methods: Two-day-old Sprague-Dawley neonatal rats were randomly divided into five groups: sham operation group, WMI group, and hUC-MSCs groups (low dose, medium dose, and high dose), with 24 rats in each group. Twenty-four hours after successful establishment of the neonatal rat white matter injury model, the WMI group was injected with sterile PBS via the lateral ventricle, while the hUC-MSCs groups received injections of hUC-MSCs at different doses. At 14 and 21 days post-modeling, hematoxylin and eosin staining was used to observe pathological changes in the tissues around the lateral ventricles. Real-time quantitative polymerase chain reaction was used to detect the quantitative expression of myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) mRNA in the brain tissue. Immunohistochemistry was employed to observe the expression levels of GFAP and neuron-specific nuclear protein (NeuN) in the tissues around the lateral ventricles. TUNEL staining was used to observe cell apoptosis in the tissues around the lateral ventricles. At 21 days post-modeling, the Morris water maze test was used to observe the spatial learning and memory capabilities of the neonatal rats., Results: At 14 and 21 days post-modeling, numerous cells with nuclear shrinkage and rupture, as well as disordered arrangement of nerve fibers, were observed in the tissues around the lateral ventricles of the WMI group and the low dose group. Compared with the WMI group, the medium and high dose groups showed alleviated pathological changes; the arrangement of nerve fibers in the medium dose group was relatively more orderly compared with the high dose group. Compared with the WMI group, there was no significant difference in the expression levels of MBP and GFAP mRNA in the low dose group ( P >0.05), while the expression levels of MBP mRNA increased and GFAP mRNA decreased in the medium and high dose groups. The expression level of MBP mRNA in the medium dose group was higher than that in the high dose group, and the expression level of GFAP mRNA in the medium dose group was lower than that in the high dose group ( P <0.05). Compared with the WMI group, there was no significant difference in the protein expression of GFAP and NeuN in the low dose group ( P >0.05), while the expression of NeuN protein increased and GFAP protein decreased in the medium and high dose groups. The expression of NeuN protein in the medium dose group was higher than that in the high dose group, and the expression of GFAP protein in the medium dose group was lower than that in the high dose group ( P <0.05). Compared with the WMI group, there was no significant difference in the number of apoptotic cells in the low dose group ( P >0.05), while the number of apoptotic cells in the medium and high dose groups was less than that in the WMI group, and the number of apoptotic cells in the medium dose group was less than that in the high dose group ( P <0.05). Compared with the WMI group, there was no significant difference in the escape latency time in the low dose group ( P >0.05); starting from the third day of the latency period, the escape latency time in the medium dose group was less than that in the WMI group ( P <0.05). The medium and high dose groups crossed the platform more times than the WMI group ( P <0.05)., Conclusions: Low dose hUC-MSCs may yield unsatisfactory repair effects on WMI in neonatal rats, while medium and high doses of hUC-MSCs have significant repair effects, with the medium dose demonstrating superior efficacy.
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- 2024
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32. GFAP-isoforms in the nervous system: Understanding the need for diversity.
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de Reus AJEM, Basak O, Dykstra W, van Asperen JV, van Bodegraven EJ, and Hol EM
- Subjects
- Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein metabolism, Protein Isoforms genetics, Gene Expression Regulation, Intermediate Filaments metabolism, Astrocytes metabolism, Astrocytes pathology
- Abstract
Glial fibrillary acidic protein (GFAP) is an intermediate filament (IF) protein expressed in specific types of glial cells in the nervous system. The expression of GFAP is highly regulated during brain development and in neurological diseases. The presence of distinct GFAP-isoforms in various cell types, developmental stages, and diseases indicates that GFAP (post-)transcriptional regulation has a role in glial cell physiology and pathology. GFAP-isoforms differ in sub-cellular localisation, IF-network assembly properties, and IF-dynamics which results in distinct molecular interactions and mechanical properties of the IF-network. Therefore, GFAP (post-)transcriptional regulation is likely a mechanism by which radial glia, astrocytes, and glioma cells can modulate cellular function., Competing Interests: Declaration of competing interest Nothing to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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33. Leukodystrophy with Macrocephaly, Refractory Epilepsy, and Severe Hyponatremia-The Neonatal Type of Alexander Disease.
- Author
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Paprocka J, Nowak M, Machnikowska-Sokołowska M, Rutkowska K, and Płoski R
- Subjects
- Child, Infant, Newborn, Humans, Glial Fibrillary Acidic Protein genetics, Alexander Disease genetics, Alexander Disease pathology, Drug Resistant Epilepsy, Hyponatremia, Spasms, Infantile, Bone Diseases, Demyelinating Diseases, Lysosomal Storage Diseases, Megalencephaly genetics
- Abstract
Introduction: Alexander disease (AxD) is a rare neurodegenerative condition that represents the group of leukodystrophies. The disease is caused by GFAP mutation. Symptoms usually occur in the infantile age with macrocephaly, developmental deterioration, progressive quadriparesis, and seizures as the most characteristic features. In this case report, we provide a detailed clinical description of the neonatal type of AxD., Method: Next-Generation Sequencing (NGS), including a panel of 49 genes related to Early Infantile Epileptic Encephalopathy (EIEE), was carried out, and then Whole Exome Sequencing (WES) was performed on the proband's DNA extracted from blood., Case Description: In the first weeks of life, the child presented with signs of increased intracranial pressure, which led to ventriculoperitoneal shunt implementation. Recurrent focal-onset motor seizures with secondary generalization occurred despite phenobarbital treatment. Therapy was modified with multiple anti-seizure medications. In MRI contrast-enhanced lesions in basal ganglia, midbrain and cortico-spinal tracts were observed. During the diagnostic process, GLUT-1 deficiency, lysosomal storage disorders, organic acidurias, and fatty acid oxidation defects were excluded. The NGS panel of EIEE revealed no abnormalities. In WES analysis, GFAP missense heterozygous variant NM_002055.5: c.1187C>T, p.(Thr396Ile) was detected, confirming the diagnosis of AxD., Conclusion: AxD should be considered in the differential diagnosis in all neonates with progressive, intractable seizures accompanied by macrocephaly.
- Published
- 2024
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34. In vivo imaging of astrocytes in the whole brain with engineered AAVs and diffusion-weighted magnetic resonance imaging.
- Author
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Li M, Liu Z, Wu Y, Zheng N, Liu X, Cai A, Zheng D, Zhu J, Wu J, Xu L, Li X, Zhu LQ, Manyande A, Xu F, and Wang J
- Subjects
- Animals, Humans, Glial Fibrillary Acidic Protein metabolism, Glial Fibrillary Acidic Protein genetics, Green Fluorescent Proteins metabolism, Green Fluorescent Proteins genetics, Male, Aquaporin 1 metabolism, Aquaporin 1 genetics, Rats, Promoter Regions, Genetic, Cells, Cultured, Transduction, Genetic methods, Astrocytes metabolism, Dependovirus genetics, Brain metabolism, Brain diagnostic imaging, Genetic Vectors administration & dosage, Diffusion Magnetic Resonance Imaging methods
- Abstract
Astrocytes constitute a major part of the central nervous system and the delineation of their activity patterns is conducive to a better understanding of brain network dynamics. This study aimed to develop a magnetic resonance imaging (MRI)-based method in order to monitor the brain-wide or region-specific astrocytes in live animals. Adeno-associated virus (AAVs) vectors carrying the human glial fibrillary acidic protein (GFAP) promoter driving the EGFP-AQP1 (Aquaporin-1, an MRI reporter) fusion gene were employed. The following steps were included: constructing recombinant AAV vectors for astrocyte-specific expression, detecting MRI reporters in cell culture, brain regions, or whole brain following cell transduction, stereotactic injection, or tail vein injection. The astrocytes were detected by both fluorescent imaging and Diffusion-weighted MRI. The novel AAV mutation (Site-directed mutagenesis of surface-exposed tyrosine (Y) residues on the AAV5 capsid) significantly increased fluorescence intensity (p < 0.01) compared with the AAV5 wild type. Transduction of the rAAV2/5 carrying AQP1 induced the titer-dependent changes in MRI contrast in cell cultures (p < 0.05) and caudate-putamen (CPu) in the brain (p < 0.05). Furthermore, the MRI revealed a good brain-wide alignment between AQP1 levels and ADC signals, which increased over time in most of the transduced brain regions. In addition, the rAAV2/PHP.eB serotype efficiently introduced AOP1 expression in the whole brain via tail vein injection. This study provides an MRI-based approach to detect dynamic changes in astrocytes in live animals. The novel in vivo tool could help us to understand the complexity of neuronal and glial networks in different pathophysiological conditions., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2024
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35. [Clinical features and pathogenesis of Glial fibrillary acidic protein (GFAP) antibody-associated disorders].
- Author
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Kimura A
- Subjects
- Humans, Glial Fibrillary Acidic Protein genetics, Brain, Autoantibodies cerebrospinal fluid, Astrocytes pathology, Meningoencephalitis diagnosis, Myelitis
- Abstract
Glial fibrillary acidic protein (GFAP) antibody-associated disorders (AD) were recently proposed to be immune-mediated neurological disorders. The pathogenesis of GFAP antibody-AD is poorly understood. Pathologically, there is a marked infiltration of large numbers of lymphocytes, including CD8+ and CD4+ T cells, into the meningeal and brain parenchyma, especially around the perivascular areas. GFAP-specific cytotoxic T cells are considered to be the effector cells of GFAP antibody-AD. The common phenotype of GFAP antibody-AD includes meningoencephalitis with or without myelitis. During the clinical disease course, patients present with consciousness disturbances, urinary dysfunction, movement disorders, meningeal irritation, and cognitive dysfunction. The detection of GFAP antibodies in the cerebrospinal fluid (CSF) by cell-based assay is essential for a diagnosis of GFAP antibody-AD. The CSF can be examined for lymphocyte-predominant pleocytosis and elevated protein levels. Brain linear perivascular radial enhancement patterns are observed in about half of GFAP antibody-AD patients. Spinal cord magnetic resonance imaging is used to detect longitudinal extensive spinal cord lesions. Although corticosteroid therapy is generally effective, some patients have a poor prognosis and relapse.
- Published
- 2024
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36. Fentanyl dysregulates neuroinflammation and disrupts blood-brain barrier integrity in HIV-1 Tat transgenic mice.
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Rademeyer KM, R Nass S, Jones AM, Ohene-Nyako M, Hauser KF, and McRae M
- Subjects
- Animals, Mice, HIV Infections virology, HIV Infections genetics, HIV Infections pathology, HIV Infections drug therapy, Disease Models, Animal, Analgesics, Opioid pharmacology, Analgesics, Opioid adverse effects, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein metabolism, Tight Junction Proteins metabolism, Tight Junction Proteins genetics, Humans, Brain drug effects, Brain virology, Brain metabolism, Brain pathology, Opioid-Related Disorders genetics, Opioid-Related Disorders pathology, Opioid-Related Disorders metabolism, Blood-Brain Barrier drug effects, Blood-Brain Barrier metabolism, Blood-Brain Barrier pathology, Blood-Brain Barrier virology, Mice, Transgenic, Fentanyl pharmacology, HIV-1 drug effects, HIV-1 genetics, tat Gene Products, Human Immunodeficiency Virus genetics, tat Gene Products, Human Immunodeficiency Virus metabolism, Neuroinflammatory Diseases genetics, Neuroinflammatory Diseases pathology, Neuroinflammatory Diseases virology
- Abstract
Opioid overdose deaths have dramatically increased by 781% from 1999 to 2021. In the setting of HIV, opioid drug abuse exacerbates neurotoxic effects of HIV in the brain, as opioids enhance viral replication, promote neuronal dysfunction and injury, and dysregulate an already compromised inflammatory response. Despite the rise in fentanyl abuse and the close association between opioid abuse and HIV infection, the interactive comorbidity between fentanyl abuse and HIV has yet to be examined in vivo. The HIV-1 Tat-transgenic mouse model was used to understand the interactive effects between fentanyl and HIV. Tat is an essential protein produced during HIV that drives the transcription of new virions and exerts neurotoxic effects within the brain. The Tat-transgenic mouse model uses a glial fibrillary acidic protein (GFAP)-driven tetracycline promoter which limits Tat production to the brain and this model is well used for examining mechanisms related to neuroHIV. After 7 days of fentanyl exposure, brains were harvested. Tight junction proteins, the vascular cell adhesion molecule, and platelet-derived growth factor receptor-β were measured to examine the integrity of the blood brain barrier. The immune response was assessed using a mouse-specific multiplex chemokine assay. For the first time in vivo, we demonstrate that fentanyl by itself can severely disrupt the blood-brain barrier and dysregulate the immune response. In addition, we reveal associations between inflammatory markers and tight junction proteins at the blood-brain barrier., (© 2024. The Author(s) under exclusive licence to The Journal of NeuroVirology, Inc.)
- Published
- 2024
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37. Substitution of Glu to Lys at Codon 332 on the GFAP Gene Alone Is Causative for Adult-onset Alexander Disease.
- Author
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Sanjo N, Suzuki M, Yoshihama R, Toyoshima Y, Mizuta I, Fujita N, Usuda H, Uchiyama Y, Yasuda R, Yoshida T, Yamada M, and Yokota T
- Subjects
- Humans, Male, Middle Aged, Codon genetics, Glial Fibrillary Acidic Protein genetics, Magnetic Resonance Imaging methods, Medulla Oblongata diagnostic imaging, Medulla Oblongata pathology, Mutation, Alexander Disease diagnostic imaging, Alexander Disease genetics
- Abstract
A 57-year-old man whose mother had been pathologically diagnosed with Alexander disease (ALXDRD), presented with cerebellar ataxia, pyramidal signs, and mild dysarthria. Brain magnetic resonance imaging revealed typical ALXDRD alterations, such as atrophy of the medulla oblongata (MO) and cervical spinal cord, a reduced sagittal diameter of the MO, and garland-like hyperintensity signals along the lateral ventricular walls. A genetic analysis of GFAP by Sanger sequencing revealed a single heterozygous mutation of Glu to Lys at codon 332 (c.994G>A) in the GFAP gene. Our results newly confirmed that p.E332K alone is the pathogenic causative mutation for adult-onset ALXDRD.
- Published
- 2024
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38. Astrocyte S100β expression and selective differentiation to GFAP and GS in the entorhinal cortex during ageing in the 3xTg-Alzheimer's disease mouse model.
- Author
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Rodríguez JJ, Gardenal E, Zallo F, Arrue A, Cabot J, and Busquets X
- Subjects
- Animals, Humans, Infant, Mice, Astrocytes metabolism, Disease Models, Animal, Entorhinal Cortex metabolism, Entorhinal Cortex pathology, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein metabolism, Glutamate-Ammonia Ligase genetics, Glutamate-Ammonia Ligase metabolism, Mice, Transgenic, Alzheimer Disease genetics, Alzheimer Disease drug therapy, Alzheimer Disease metabolism
- Abstract
The study of astrocytes and its role in the development and evolution of neurodegenerative diseases, including Alzheimer's disease (AD) is essential to fully understand their aetiology. The aim if this study is to deepen into the concept of the heterogeneity of astrocyte subpopulations in the EC and in particular the identification of differentially functioning astrocyte subpopulations that respond differently to AD progression. S100β protein belongs to group of small calcium regulators of cell membrane channels and pumps that are expressed by astrocytes and is hypothesised to play and have a relevant role in AD development. We analysed the selective differentiation of S100β-positive astrocytes into Glutamine synthetase (GS) and Glial fibrillary acidic protein (GFAP)-positive sub-groups in the entorhinal cortex (EC) of AD triple transgenic animal model (3xTg-AD). EC is the brain region earliest affected in humans AD but also in this closest animal model regarding their pathology and time course. We observed no changes in the number of S100β-positive astrocytes between 1 and 18 months of age in the EC of 3xTg-AD mice. However, we identified relevant morphological changes in S100β/GFAP positive astrocytes showing a significant reduction in their surface and volume whilst an increase in number and percentage. Furthermore, the percentage of S100β/GS positive astrocyte population was also increased in 18 months old 3xTg-AD mice compared to the non-Tg mice. Our findings reveal the presence of differentially controlled astrocyte populations that respond differently to AD progression in the EC of 3xTg-AD mice. These results highpoints the major astrocytic role together with its early and marked affection in AD and arguing in favour of its importance in neurogenerative diseases and potential target for new therapeutic approaches., Competing Interests: Declaration of Competing Interest All authors declare no actual or potential conflicts of interest including any financial, personal or other relationship with other people or organizations that could inappropriately influence the present work., (Copyright © 2023. Published by Elsevier GmbH.)
- Published
- 2024
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39. Alexander disease genetics: Beyond GFAP exon sequencing?
- Author
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Cypers G
- Subjects
- Humans, Glial Fibrillary Acidic Protein genetics, Brain, Exons, Mutation, Alexander Disease genetics
- Published
- 2023
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40. Authors' response to: "Alexander disease genetics: Beyond GFAP exon sequencing?"
- Author
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Alexander AL, Lim SY, Massingham LJ, Phillips O, Chambers MK, and Donahue JE
- Subjects
- Humans, Glial Fibrillary Acidic Protein genetics, Brain, Exons, Mutation, Alexander Disease genetics
- Published
- 2023
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41. Plasma Biomarker Profile and Clinical Correlations in Adult Patients With Tuberous Sclerosis Complex.
- Author
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Orlando B, Morano A, Manzini V, Cerulli Irelli E, Borioni MS, Veroni C, Salamone EM, D'Amelio C, Moliterni E, Giustini S, Ruffolo G, Arisi I, D'Onofrio M, Giallonardo AT, Piscopo P, and Di Bonaventura C
- Subjects
- Male, Female, Humans, Adult, Biomarkers, Astrocytes, Genotype, Glial Fibrillary Acidic Protein genetics, Autism Spectrum Disorder genetics, Tuberous Sclerosis genetics
- Abstract
Objectives: Different pathophysiologic mechanisms, especially involving astrocytes, could contribute to tuberous sclerosis complex (TSC). We assessed neurodegeneration and astrocytopathy plasma biomarkers in adult patients with TSC to define TSC biomarker profile and investigate clinical-radiologic correlations., Methods: Patients with TSC aged 15 years or older followed at Policlinico "Umberto I" of Rome were consecutively enrolled (July 2021-June 2022). The plasma levels of the following biomarkers were compared between patients and age/sex-matched healthy controls (HCs): tTau, pTau181, Abeta
40 , Abeta42 , neurofilament light chain, and glial fibrillary acid protein (GFAP)., Results: Thirty-one patients (20 females/11 males; median age 30 years, interquartile range 24-47) and 38 HCs were enrolled. Only GFAP was significantly higher in the whole TSC population than in HCs (132.71 [86.14-231.06] vs 44.80 [32.87-66.76] pg/mL, p < 0.001), regardless of genotype. GFAP correlated with the disease clinical (ρ = 0.498, p = 0.005) and radiologic severity (ρ = 0.417, p = 0.001). It was significantly higher in patients with epileptic spasms (254.50 [137.54-432.96] vs 86.92 [47.09-112.76] pg/mL, p < 0.0001), moderate-severe intellectual disability (200.80 [78.40-427.6] vs 105.08 [46.80-152.58] pg/mL, p = 0.040), and autism spectrum disorder (306.26 [159.07-584.47] vs 109.34 [72.56-152.08] pg/mL, p = 0.021)., Discussion: Our exploratory study documented a significant increase of GFAP plasma concentration in adult patients with TSC, correlated with their neurologic severity, supporting the central role of astrocytopathy in TSC pathophysiology., (© 2023 American Academy of Neurology.)- Published
- 2023
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42. Characterisation of GFAP-Expressing Glial Cells in the Dorsal Root Ganglion after Spared Nerve Injury.
- Author
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Konnova EA, Deftu AF, Chu Sin Chung P, Pertin M, Kirschmann G, Decosterd I, and Suter MR
- Subjects
- Animals, Mice, Ganglia, Spinal metabolism, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein metabolism, Neuroglia metabolism, Satellite Cells, Perineuronal metabolism, Neuralgia metabolism, Trauma, Nervous System metabolism
- Abstract
Satellite glial cells (SGCs), enveloping primary sensory neurons' somas in the dorsal root ganglion (DRG), contribute to neuropathic pain upon nerve injury. Glial fibrillary acidic protein (GFAP) serves as an SGC activation marker, though its DRG satellite cell specificity is debated. We employed the hGFAP-CFP transgenic mouse line, designed for astrocyte studies, to explore its expression within the peripheral nervous system (PNS) after spared nerve injury (SNI). We used diverse immunostaining techniques, Western blot analysis, and electrophysiology to evaluate GFAP+ cell changes. Post-SNI, GFAP+ cell numbers increased without proliferation, and were found near injured ATF3+ neurons. GFAP+ FABP7+ SGCs increased, yet 75.5% of DRG GFAP+ cells lacked FABP7 expression. This suggests a significant subset of GFAP+ cells are non-myelinating Schwann cells (nmSC), indicated by their presence in the dorsal root but not in the ventral root which lacks unmyelinated fibres. Additionally, patch clamp recordings from GFAP+ FABP7-cells lacked SGC-specific K
ir 4.1 currents, instead displaying outward Kv currents expressing Kv 1.1 and Kv 1.6 channels specific to nmSCs. In conclusion, this study demonstrates increased GFAP expression in two DRG glial cell subpopulations post-SNI: GFAP+ FABP7+ SGCs and GFAP+ FABP7- nmSCs, shedding light on GFAP's specificity as an SGC marker after SNI.- Published
- 2023
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43. Acute onset of adult Alexander disease and the concept of GFAP toxicity.
- Author
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Godinho F, Guerreiro C, Parente Freixo J, Oliveira J, and Lourenço Rosa J
- Subjects
- Adult, Humans, Glial Fibrillary Acidic Protein genetics, Magnetic Resonance Imaging, Mutation, Alexander Disease complications, Alexander Disease diagnostic imaging, Alexander Disease genetics
- Abstract
Competing Interests: Declaration of Competing Interest The authors did not receive support from any organization for the submitted work. The authors have no competing interests to declare that are relevant to the content of this article.
- Published
- 2023
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44. Adult-onset Alexander disease among patients of Jewish Syrian descent.
- Author
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Anis S, Fay-Karmon T, Lassman S, Shbat F, Lesman-Segev O, Mor N, Barel O, Dominissini D, Chorin O, Pras E, Greenbaum L, and Hassin-Baer S
- Subjects
- Female, Humans, Adult, Middle Aged, Jews genetics, Syria, Glial Fibrillary Acidic Protein genetics, Mutation, Atrophy, Alexander Disease diagnostic imaging, Alexander Disease genetics
- Abstract
Alexander disease (AxD) is a rare autosomal dominant leukodystrophy caused by heterozygous mutations in the glial fibrillary acid protein (GFAP) gene. The age of symptoms onset ranges from infancy to adulthood, with variable clinical and radiological manifestations. Adult-onset AxD manifests as a chronic and progressive condition, characterized by bulbar, motor, cerebellar, and other clinical signs and symptoms. Neuroradiological findings typically involve the brainstem and cervical spinal cord. Adult-onset AxD has been described in diverse populations but is rare in Israel. We present a series of patients diagnosed with adult-onset AxD from three families, all of Jewish Syrian descent. Five patients (4 females) were diagnosed with adult-onset AxD due to the heterozygous mutation c.219G > A, p.Met73Ile in GFAP. Age at symptoms onset ranged from 48 to 61 years. Clinical characteristics were typical and involved progressive bulbar and gait disturbance, followed by pyramidal and cerebellar impairment, dysautonomia, and cognitive decline. Imaging findings included medullary and cervical spinal atrophy and mostly infratentorial white matter hyperintensities. A newly recognized cluster of adult-onset AxD in Jews of Syrian origin is presented. This disorder should be considered in differential diagnosis in appropriate circumstances. Genetic counselling for family members is required in order to discuss options for future family planning., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2023
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45. Fate Specification of GFAP-Negative Primitive Neural Stem Cells and Their Progeny at Clonal Resolution.
- Author
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Yammine SZ, Burns I, Gosio J, Peluso A, Merritt DM, Innes B, Coles BLK, Yan WR, Bader GD, Morshead CM, and van der Kooy D
- Subjects
- Mice, Animals, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein metabolism, Neurons metabolism, Brain metabolism, Astrocytes metabolism, Cell Differentiation genetics, Neural Stem Cells metabolism
- Abstract
The mature brain contains an incredible number and diversity of cells that are produced and maintained by heterogeneous pools of neural stem cells (NSCs). Two distinct types of NSCs exist in the developing and adult mouse brain: Glial Fibrillary Acidic Protein (GFAP)-negative primitive (p)NSCs and downstream GFAP-positive definitive (d)NSCs. To better understand the embryonic functions of NSCs, we performed clonal lineage tracing within neurospheres grown from either pNSCs or dNSCs to enrich for their most immediate downstream neural progenitor cells (NPCs). These clonal progenitor lineage tracing data allowed us to construct a hierarchy of progenitor subtypes downstream of pNSCs and dNSCs that were then validated using single-cell transcriptomics. Further, we identify Nexn as required for neuronal specification from neuron/astrocyte progenitor cells downstream of rare pNSCs. Combined, these data provide single-cell resolution of NPC lineages downstream of rare pNSCs that likely would be missed from population-level analyses in vivo.
- Published
- 2023
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46. Adult-onset Alexander disease with brainstem and cervical cord enhancing lesions.
- Author
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Oliveira DA, Araújo LC, Paiva ARB, and Melo ES
- Subjects
- Male, Humans, Adult, Glial Fibrillary Acidic Protein genetics, Brain Stem diagnostic imaging, Brain Stem pathology, Magnetic Resonance Imaging methods, Alexander Disease complications, Alexander Disease diagnostic imaging, Alexander Disease genetics, Cervical Cord pathology
- Abstract
Leukodystrophies are a group of genetic diseases with diverse clinical features and prominent involvement of the central nervous system white matter. We describe a 27-year-old man who presented with a progressive neurological disease, and striking involvement of the brainstem and symmetrical white matter lesions on MR scanning. Having excluded several other causes of leukodystrophy, we confirmed Alexander disease when a genetic panel showed a probable pathogenic variant in GFAP : p.Leu359Pro. Clinicians should suspect Alexander disease in people with a progressive neurological motor decline who has pyramidal and bulbar signs and compatible neuroimaging., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
- Full Text
- View/download PDF
47. Overlapping Epstein-Barr virus encephalitis and autoimmune glial fibrillary acidic protein astrocytopathy.
- Author
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Zhang JR, Zhuang S, Xu XD, Song WL, Li KR, Jiang Y, Cheng XY, Shi JJ, Hu WD, Liu CF, and Zhang YL
- Subjects
- Humans, Antibodies, Autoantibodies, Herpesvirus 4, Human, Immunoglobulins, Intravenous, Methylprednisolone therapeutic use, Glucocorticoids therapeutic use, Diagnosis, Differential, Astrocytes immunology, Astrocytes metabolism, Encephalitis complications, Encephalitis immunology, Encephalitis therapy, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections therapy, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein immunology, Autoimmune Diseases of the Nervous System complications, Autoimmune Diseases of the Nervous System diagnosis, Autoimmune Diseases of the Nervous System therapy
- Abstract
We describe three cases of overlapping Epstein-Barr virus (EBV) Encephalitis and Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy (GFAP-A). The three cases all presented with initial symptoms of fever, headache, coma, and posture tremor of the upper limbs, then followed by limb weakness and dysuria. All of the three cases were on ventilators. Case 1 and 2 improved dramatically after intravenous methylprednisoloneand immunoglobulin treatment. However, case 3 presented dyspneic, and died from gastrointestinal hemorrhage. The GFAP-A triggered by EBV intracranial infection could initially masquerade as EBV encephalitis only, and the detection of GFAP antibody is essential for differentiation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)
- Published
- 2023
- Full Text
- View/download PDF
48. Fetal-onset Alexander disease with radiological-neuropathological correlation.
- Author
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Devos J, Devriendt K, Richter J, Jansen K, Baldewijns M, Thal DR, and Aertsen M
- Subjects
- Pregnancy, Female, Humans, Glial Fibrillary Acidic Protein genetics, Cerebral Ventricles pathology, Radiography, Mutation, Magnetic Resonance Imaging, Alexander Disease diagnostic imaging, Alexander Disease genetics, Alexander Disease pathology
- Abstract
Alexander disease is a leukodystrophy caused by mutations in the GFAP gene, primarily affecting the astrocytes. This report describes the prenatal and post-mortem neuroimaging findings in a case of genetically confirmed, fetal-onset Alexander disease with pathological correlation after termination of pregnancy. The additional value of fetal brain magnetic resonance imaging in the third trimester as a complementary evaluation tool to neurosonography is shown for suspected cases of fetal-onset Alexander disease. Diffuse signal abnormalities of the periventricular white matter in association with thickening of the fornix and optic chiasm can point towards the diagnosis. Furthermore, the presence of atypical imaging findings such as microcephaly and cortical folding abnormalities in this case broadens our understanding of the phenotypic variability of Alexander disease., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2023
- Full Text
- View/download PDF
49. The human RAP1 and GFAPɛ proteins increase γ-secretase activity in a yeast model system.
- Author
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Swanson MJ, Lewis KN, Carpenter R, Whetzel A, and Bae NS
- Subjects
- Humans, Amyloid beta-Peptides genetics, Amyloid Precursor Protein Secretases genetics, Amyloid Precursor Protein Secretases metabolism, Glial Fibrillary Acidic Protein genetics, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Shelterin Complex, Telomere-Binding Proteins genetics, Transcription Factors genetics, Alzheimer Disease genetics, Neuroblastoma, Saccharomyces cerevisiae Proteins genetics
- Abstract
Alzheimer's disease (AD) is an age-related disorder that results in progressive cognitive impairment and memory loss. Deposition of amyloid β (Aβ) peptides in senile plaques is a hallmark of AD. γ-secretase produces Aβ peptides, mostly as the soluble Aβ40 with fewer insoluble Aβ42 peptides. Rare, early-onset AD (EOAD) occurs in individuals under 60 years of age. Most EOAD cases are due to unknown genetic causes, but a subset is due to mutations in the genes encoding the amyloid precursor protein that is processed into Aβ peptides or the presenilins (PS1 and PS2) that process APP. PS1 interacts with the epsilon isoform of glial fibrillary acidic protein (GFAPɛ), a protein found in the subventricular zone of the brain. We have found that GFAPɛ interacts with the telomere protection factor RAP1 (TERF2IP). RAP1 can also interact with PS1 alone or with GFAPɛ in vitro. Our data show that the nuclear protein RAP1 has an extratelomeric role in the cytoplasm through its interactions with GFAPɛ and PS1. GFAPɛ coprecipitated with RAP1 from human cell extracts. RAP1, GFAPɛ, and PS1 all colocalized in human SH-SY5Y cells. Using a genetic model of the γ-secretase complex in Saccharomyces cerevisiae, RAP1 increased γ-secretase activity, and this was potentiated by GFAPɛ. Our studies are the first to connect RAP1 with an age-related disorder., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Genetics Society of America.)
- Published
- 2023
- Full Text
- View/download PDF
50. Adult-onset Alexander disease with unusual inflammatory features and a novel GFAP mutation in two patients.
- Author
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Ziad F, Cypers G, Phillips M, Vanhoenacker P, Hostens A, Yadavraj S, Lamont D, and Robertson T
- Subjects
- Adult, Humans, Brain diagnostic imaging, Glial Fibrillary Acidic Protein genetics, Magnetic Resonance Imaging, Mutation, Alexander Disease genetics
- Published
- 2023
- Full Text
- View/download PDF
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