ASN NEURO最新文献

{"title":"Quantitative Analysis of Early White Matter Damage in Cuprizone Mouse Model of Demyelination Using 7.0 T MRI Multiparametric Approach.","authors":"Emma Friesen, Maxina Sheft, Kamya Hari, Vanessa Palmer, Shenghua Zhu, Sheryl Herrera, Richard Buist, Depeng Jiang, Xin-Min Li, Marc R Del Bigio, Jonathan D Thiessen, Melanie Martin","doi":"10.1080/17590914.2024.2404366","DOIUrl":"10.1080/17590914.2024.2404366","url":null,"abstract":"<p><p>Magnetic Resonance Imaging (MRI) is commonly used to follow the progression of neurodegenerative conditions, including multiple sclerosis (MS). MRI is limited by a lack of correlation between imaging results and clinical presentations, referred to as the clinico-radiological paradox. Animal models are commonly used to mimic the progression of human neurodegeneration and as a tool to help resolve the paradox. Most studies focus on later stages of white matter (WM) damage whereas few focus on early stages when oligodendrocyte apoptosis has just begun. The current project focused on these time points, namely weeks 2 and 3 of cuprizone (CPZ) administration, a toxin which induces pathophysiology similar to MS. <i>In vivo</i> T₂-weighted (T₂W) and Magnetization Transfer Ratio (MTR) maps and <i>ex vivo</i> Diffusion Tensor Imaging (DTI), Magnetization Transfer Imaging (MTI), and relaxometry (T₁ and T₂) values were obtained at 7 T. Significant changes in T₂W signal intensity and non-significant changes in MTR were observed to correspond to early WM damage, whereas significant changes in both corresponded with full demyelination. Some DTI metrics decrease with simultaneous increase in others, indicating acute demyelination. MTI metrics T₂^A, T₂^B, <i>f</i> and R were observed to have contradictory changes across CPZ administration. T₁ relaxation times were observed to have stronger correlations to disease states during later stages of CPZ treatment, whereas T₂ had weak correlations to early WM damage. These results all suggest the need for multiple metrics and further studies at early and late time points of demyelination. Further research is required to continue investigating the interplay between various MR metrics during all weeks of CPZ administration.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"16 1","pages":"2404366"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abnormal Regulation of Mitochondrial Sphingolipids during Aging and Alzheimer's Disease.","authors":"Simone M Crivelli, Zainuddin Quadri, Ahmed Elsherbini, Hemendra J Vekaria, Patrick G Sullivan, Wenbo Zhi, Pilar Martinez-Martinez, Stefka D Spassieva, Erhard Bieberich","doi":"10.1080/17590914.2024.2404367","DOIUrl":"10.1080/17590914.2024.2404367","url":null,"abstract":"<p><p>During pathogenesis of Alzheimer's disease (AD), mitochondria suffer alterations that lead to low energy production and reactive oxygen species formation. However, the mechanism of impaired mitochondria homeostasis in AD is not fully understood. We hypothesized that abnormal sphingolipid metabolism in mitochondria could be one of the contributing factors to mitochondrial dysfunction. Synaptic and non-synaptic mitochondria were isolated from 5xFAD and wild type (WT) mice at 3 and 7 months using Ficoll gradient ultracentrifugation, and their function was analyzed using Seahorse assay. Additionally, mitochondria were analyzed using mass spectrometry for proteomics and sphingolipidomics analyses. Sphingolipid levels were also determined in synaptic and non-synaptic mitochondria isolated from AD patients and healthy controls. We found that synaptic mitochondria isolated from 3-months old 5xFAD mice manifest diminished oxygen consumption as compared to WT. Consistently, proteomics analysis showed that proteins related to respiratory electron transport and oxidative phosphorylation were altered in 5xFAD mice. When quantifying the main sphingolipids in mitochondria, we found that Cer 18:0, Cer 22:0, and Cer 24:1 were increased already at 3 months in 5xFAD mice. No increase in ceramides was detected in mitochondria isolated from AD patients. However, increased levels of sphingosine were found in both 5xFAD mice and AD patients when compared to respective controls. We report that the regulation of sphingolipids in mitochondria is abnormal at 3 months of age in 5xFAD mice, as indicated by the accumulation of long-chain ceramides, which increases with age. Sphingosine levels are increased in both the mitochondria of 5xFAD mice and AD patients. Our data suggest that the sphingolipid composition is dysregulated in mitochondria early during AD pathogenesis.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"16 1","pages":"2404367"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells.","authors":"Derek C Lee, Linh Ta, Purna Mukherjee, Tomas Duraj, Marek Domin, Bennett Greenwood, Srada Karmacharya, Niven R Narain, Michael Kiebish, Christos Chinopoulos, Thomas N Seyfried","doi":"10.1080/17590914.2024.2422268","DOIUrl":"10.1080/17590914.2024.2422268","url":null,"abstract":"<p><p>Energy is necessary for tumor cell viability and growth. Aerobic glucose-driven lactic acid fermentation is a common metabolic phenotype seen in most cancers including malignant gliomas. This metabolic phenotype is linked to abnormalities in mitochondrial structure and function. A luciferin-luciferase bioluminescence ATP assay was used to measure the influence of amino acids, glucose, and oxygen on ATP content and viability in mouse (VM-M3 and CT-2A) and human (U-87MG) glioma cells that differed in cell biology, genetic background, and species origin. Oxygen consumption was measured using the Resipher system. Extracellular lactate and succinate were measured as end products of the glycolysis and glutaminolysis pathways, respectively. The results showed that: (1) glutamine was a source of ATP content irrespective of oxygen. No other amino acid could replace glutamine in sustaining ATP content and viability; (2) ATP content persisted in the absence of glucose and under hypoxia, ruling out substantial contribution through either glycolysis or oxidative phosphorylation (OxPhos) under these conditions; (3) Mitochondrial complex IV inhibition showed that oxygen consumption was not an accurate measure for ATP production through OxPhos. The glutaminase inhibitor, 6-diazo-5-oxo-L-norleucine (DON), reduced ATP content and succinate export in cells grown in glutamine. The data suggests that mitochondrial substrate level phosphorylation in the glutamine-driven glutaminolysis pathway contributes to ATP content in these glioma cells. A new model is presented highlighting the synergistic interaction between the high-throughput glycolysis and glutaminolysis pathways that drive malignant glioma growth and maintain ATP content through the aerobic fermentation of both glucose and glutamine.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"16 1","pages":"2422268"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Robert Paul Skoff (1942-2023).","authors":"Joyce Benjamins, Pamela Knapp, Anne Boullerne","doi":"10.1080/17590914.2024.2393559","DOIUrl":"10.1080/17590914.2024.2393559","url":null,"abstract":"","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"16 1","pages":"2393559"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial.","authors":"Douglas L Feinstein","doi":"10.1080/17590914.2024.2386884","DOIUrl":"10.1080/17590914.2024.2386884","url":null,"abstract":"","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"16 1","pages":"2386884"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of BR1 and BI30 AAVs for Brain Endothelial Tropism.","authors":"Felecia M Marottoli, Deebika Balu, Rohan Chaudhary, Sarah E Lutz, Leon M Tai","doi":"10.1080/17590914.2024.2427953","DOIUrl":"10.1080/17590914.2024.2427953","url":null,"abstract":"<p><p>Brain endothelial cells are critical for homeostasis of the central nervous system. Novel adeno-associated viruses (AAV) with brain endothelial cell tropism have been developed and are beginning to be employed in mechanistic and therapeutic research. Studies using AAVs can be involved in terms of cost, time and personnel, and many groups, including our own, are not experts on the technology. Therefore, it is important to report data using AAVs with the research community as a guide for ongoing and future studies. Here, we detail our initial experience with the two most prevalent AAVs with tropism for brain endothelial cells, AAV-BR1 and AAV-BI30. One of our long-term goals is to express key proteins in brain endothelial cells and determine the impact on brain function. For method development, we administered AAV-BR1 and AAV-BI30 with a CMV-driven fluorescent reporter (CMV-P2A-mCherry) to wild-type mice intravenously (retro-orbital) and measured expression in brain and peripheral tissues by RT-PCR and immunostaining. We found that AAV-BR1 transduces neurons and endothelial cells in the brain, and the lung and liver, whereas AAV-BI30 transduces brain endothelial cells and peripheral tissue. Our data highlights the importance of using the AAV best suited to the scientific question.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"16 1","pages":"2427953"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytic Ephrin-B1 Regulates Oligodendrocyte Development and Myelination.","authors":"Samantha N Sutley-Koury, Alyssa Anderson, Christopher Taitano-Johnson, Moyinoluwa Ajayi, Anna O Kulinich, Kimberly Contreras, Jasmin Regalado, Seema K Tiwari-Woodruff, Iryna M Ethell","doi":"10.1080/17590914.2024.2401753","DOIUrl":"10.1080/17590914.2024.2401753","url":null,"abstract":"<p><p>Astrocytes have been implicated in oligodendrocyte development and myelination, however, the mechanisms by which astrocytes regulate oligodendrocytes remain unclear. Our findings suggest a new mechanism that regulates astrocyte-mediated oligodendrocyte development through ephrin-B1 signaling in astrocytes. Using a mouse model, we examined the role of astrocytic ephrin-B1 signaling in oligodendrocyte development by deleting ephrin-B1 specifically in astrocytes during the postnatal days (P)14-P28 period and used mRNA analysis, immunohistochemistry, and mouse behaviors to study its effects on oligodendrocytes and myelination. We found that deletion of astrocytic ephrin-B1 downregulated many genes associated with oligodendrocyte development, myelination, and lipid metabolism in the hippocampus and the corpus callosum. Additionally, we observed a reduced number of oligodendrocytes and impaired myelination in the corpus callosum of astrocyte-specific ephrin-B1 KO mice. Finally, our data show reduced motor strength in these mice exhibiting clasping phenotype and impaired performance in the rotarod test most likely due to impaired myelination. Our studies provide new evidence that astrocytic ephrin-B1 positively regulates oligodendrocyte development and myelination, potentially through astrocyte-oligodendrocyte interactions.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"16 1","pages":"2401753"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular Mechanisms of Cognitive Enhancement: The <i>In Vivo</i> Modulation of the Firing Activity and the Responsiveness of Rat Hippocampal Neurons by Memantine and Alpha7 Nicotinic Acetylcholine Receptor Ligands.","authors":"Lili Veronika Nagy, Zsolt Kristóf Bali, István Ledneczki, Zsolt Némethy, Balázs Lendvai, István Hernádi","doi":"10.1080/17590914.2024.2371160","DOIUrl":"10.1080/17590914.2024.2371160","url":null,"abstract":"<p><p>Promising new pharmacological strategies for the enhancement of cognition target either nicotinic acetylcholine receptors (nAChR) or N-methyl-D-aspartate receptors (NMDAR). There is also an increasing interest in low-dose combination therapies co-targeting the above neurotransmitter systems to reach greater efficacy over the monotreatments and to reduce possible side effects of high-dose monotreatments. In the present study, we assessed modulatory effects of the α7 nAChR-selective agonist PHA-543613 (PHA), a novel α7 nAChR positive allosteric modulator compound (CompoundX) and the NMDAR antagonist memantine on the <i>in vivo</i> firing activity of CA1 pyramidal neurons in the rat hippocampus. Three different test conditions were applied: spontaneous firing activity, NMDA-evoked firing activity and ACh-evoked firing activity. Results showed that high but not low doses of memantine decreased NMDA-evoked firing activity, and low doses increased the spontaneous and ACh-evoked firing activity. Systemically applied PHA robustly potentiated ACh-evoked firing activity with having no effect on NMDA-evoked activity. In addition, CompoundX increased both NMDA- and ACh-evoked firing activity, having no effects on spontaneous firing of the neurons. A combination of low doses of memantine and PHA increased firing activity in all test conditions and similar effects were observed with memantine and CompoundX but without spontaneous firing activity increasing effects. Our present results demonstrate that α7 nAChR agents beneficially interact with Alzheimer's disease medication memantine. Moreover, positive allosteric modulators potentiate memantine effects on the right time and the right place without affecting spontaneous firing activity. All these data confirm previous behavioral evidence for the viability of combination therapies for cognitive enhancement.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"16 1","pages":"2371160"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced Expression of Oligodendrocyte Linage-Enriched Transcripts During the Endoplasmic Reticulum Stress/Integrated Stress Response.","authors":"Yonglin Gao, Lukasz P Slomnicki, Ewa Kilanczyk, Michael D Forston, Maciej Pietrzak, Eric C Rouchka, Russell M Howard, Scott R Whittemore, Michal Hetman","doi":"10.1080/17590914.2024.2371162","DOIUrl":"10.1080/17590914.2024.2371162","url":null,"abstract":"<p><p>Endoplasmic reticulum (ER) stress in oligodendrocyte (OL) linage cells contributes to several CNS pathologies including traumatic spinal cord injury (SCI) and multiple sclerosis. Therefore, primary rat OL precursor cell (OPC) transcriptomes were analyzed using RNASeq after treatments with two ER stress-inducing drugs, thapsigargin (TG) or tunicamycin (TM). Gene ontology term (GO) enrichment showed that both drugs upregulated mRNAs associated with the general stress response. The GOs related to ER stress were only enriched for TM-upregulated mRNAs, suggesting greater ER stress selectivity of TM. Both TG and TM downregulated cell cycle/cell proliferation-associated transcripts, indicating the anti-proliferative effects of ER stress. Interestingly, many OL lineage-enriched mRNAs were downregulated, including those for transcription factors that drive OL identity such as <i>Olig2</i>. Moreover, ER stress-associated decreases of OL-specific gene expression were found in mature OLs from mouse models of white matter pathologies including contusive SCI, toxin-induced demyelination, and Alzheimer's disease-like neurodegeneration. Taken together, the disrupted transcriptomic fingerprint of OL lineage cells may facilitate myelin degeneration and/or dysfunction when pathological ER stress persists in OL lineage cells.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"16 1","pages":"2371162"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dorsomedial Ventromedial Hypothalamic Nucleus Growth Hormone-Releasing Hormone Neuron Steroidogenic Factor-1 Gene Targets in Female Rat.","authors":"Subash Sapkota, Sagor C Roy, Karen P Briski","doi":"10.1080/17590914.2024.2403345","DOIUrl":"10.1080/17590914.2024.2403345","url":null,"abstract":"<p><p>The prospect that the ventromedial hypothalamic nucleus (VMN) transcription factor steroidogenic factor-1/NR5A1 (SF-1) may exert sex-dimorphic control of glucose counterregulation is unresolved. Recent studies in male rats show that SF-1 regulates transcription of co-expressed hypoglycemia-sensitive neurochemicals in dorsomedial VMN growth hormone-releasing hormone (Ghrh) neurons. Gene knockdown and laser-catapult-microdissection/single-cell multiplex qPCR techniques were used here in a female rat model to determine if SF-1 control of Ghrh neuron transmitter marker, energy sensor, and estrogen receptor (ER) variant mRNAs varies according to sex. Data show that in females, hypoglycemia elicits a gain of SF-1 inhibitory control of VMNdm Ghrh neuron Ghrh and Ghrh-receptor gene profiles and loss of augmentation of glutaminase transcription; SF-1 gene silencing diminished eu- and hypoglycemic patterns of neuronal nitric oxide gene transcription. SF-1 imposes divergent control of baseline and hypoglycemic glutamate decarboxylase₆₅ (GAD)-1 (stimulatory) versus GAD2 (inhibitory) mRNAs in that sex. SF-1 stimulates baseline VMNdm Ghrh neuron PRKAA1/AMPKα1 and PRKAA2/AMPKα2 gene expression, yet causes opposite changes in these gene profiles during hypoglycemia. SF-1 exerts glucose-dependent control of ER-alpha and G-protein-coupled ER-1 transcription, but blunts ER-beta gene profiles during eu- and hypoglycemia. In females, SF-1 knockdown did not affect hypercorticosteronemia or hyperglucagonemia, but blunted hypoglycemic suppression of growth hormone secretion. Results show that SF-1 expression is critical for female rat VMNdm Ghrh neuron counterregulatory neurochemical, AMPK catalytic subunit, and ER gene transcription responses to hypoglycemia. Sex differences in direction of SF-1 control of distinctive gene profiles may result in observed disparities in SF-1 regulation of counterregulatory hormone secretion between sexes.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"16 1","pages":"2403345"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}