ASN NEURO最新文献

{"title":"Understanding the Myelin <i>g</i> Ratio from First Principles, Its Derivation, Uses and Artifacts.","authors":"Alexander Gow","doi":"10.1080/17590914.2024.2445624","DOIUrl":"10.1080/17590914.2024.2445624","url":null,"abstract":"<p><p>In light of the increasing importance for measuring myelin <i>g</i> ratios - the ratio of axon-to-fiber (axon + myelin) diameters in myelin internodes - to understand normal physiology, disease states, repair mechanisms and myelin plasticity, there is urgent need to minimize processing and statistical artifacts in current methodologies. Many contemporary studies fall prey to a variety of artifacts, reducing study outcome robustness and slowing development of novel therapeutics. Underlying causes stem from a lack of understanding of the myelin <i>g</i> ratio, which has persisted more than a century. An extended exploratory data analysis from first principles (the axon-fiber diameter relation) is presented herein and has major consequences for interpreting published <i>g</i> ratio studies. Indeed, a model of the myelin internode naturally emerges because of (1) the strong positive correlation between axon and fiber diameters and (2) the demonstration that the relation between these variables is one of direct proportionality. From this model, a robust framework for data analysis, interpretation and understanding allows specific predictions about myelin internode structure under normal physiological conditions. Further, the model establishes that a regression fit to <i>g</i> ratio plots has zero slope, and it identifies the underlying causes of several data processing artifacts that can be mitigated by plotting <i>g</i> ratios against fiber diameter (not axon diameter). Hypothesis testing can then be used for extending the model and evaluating myelin internodal properties under pathophysiological conditions (forthcoming). For without a statistical model as anchor, hypothesis testing is aimless like a rudderless ship on the ocean.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2445624"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031981","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":"A Statistically-Robust Model of the Axomyelin Unit under Normal Physiologic Conditions with Application to Disease States.","authors":"Alexander Gow, Jeffrey L Dupree, Douglas L Feinstein, Anne Boullerne","doi":"10.1080/17590914.2024.2447336","DOIUrl":"10.1080/17590914.2024.2447336","url":null,"abstract":"<p><p>Despite tremendous progress in characterizing the myriad cellular structures in the nervous system, a full appreciation of the interdependent and intricate interactions between these structures is as yet unfulfilled. Indeed, few more so than the interaction between the myelin internode and its ensheathed axon. More than a half-century after the ultrastructural characterization of this axomyelin unit, we lack a reliable understanding of the physiological properties, the significance and consequence of pathobiological processes, and the means to gauge success or failure of interventions designed to mitigate disease. Herein, we highlight shortcomings in the most common statistical procedures used to characterize the myelin <i>g</i> ratio, with particular emphasis on the underlying principles of simple linear regression. These shortcomings lead to insensitive detection and/or ambiguous interpretation of normal physiology, disease mechanisms and remedial methodologies. To address these problems, we syndicate insights from early seminal myelin studies and use a statistical model of the axomyelin unit that is established in Gow (2025). Herein, we develop and demonstrate a statistically-robust analysis pipeline with which to examine and interpret axomyelin physiology and pathobiology in two disease states, experimental autoimmune encephalomyelitis and the <i>rumpshaker</i> mouse model of leukodystrophy. On a cautionary note, our pipeline is a relatively simple and streamlined approach that is not necessarily a panacea for all <i>g</i> ratio analyses. Rather, it approximates a minimum effort needed to elucidate departures from normal physiology and to determine if more comprehensive studies may lead to deeper insights.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2447336"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063471","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":"Analysis of Oligodendrocyte Lineage Cell Progression with Cre-Mediated RiboTag Reporter Lines.","authors":"George S Melchor, Maya S Shah, Zeeba Manavi, Lauren M Rosko, Jingwen Hu, Haiyang Wang, Maryna Baydyuk, Jeffrey K Huang","doi":"10.1080/17590914.2025.2513885","DOIUrl":"https://doi.org/10.1080/17590914.2025.2513885","url":null,"abstract":"<p><p>Cre-reporter strategies in transgenic mice are widely used to assess the specificity of gene promoter activities, and for fate-mapping studies during development and under injury conditions. The ribosome tagging strategy, RiboTag, is a transgenic approach, in which a hemagglutinin (HA) tag fused to the endogenous ribosomal protein, RPL22, is expressed through the Cre/loxP system. To profile RiboTag reporter expression in oligodendrocyte lineage cells (OLCs), we generated NG2^Cre:Rpl22^HA, Pdgfra^CreERT:Rpl22^HA, and Plp^CreERT:Rpl22^HA mice. We found that NG2^Cre:Rpl22^HA displayed strong HA reporter expression in OLCs and neuronal subpopulations in the postnatal CNS. Tamoxifen administration into Pdgfra^CreERT:Rpl22^HA and Plp^CreERT:Rpl22^HA mice led to widespread HA reporter expression in oligodendrocyte precursor cells (OPCs) and oligodendrocytes, respectively, throughout the brain and spinal cord. Following focal demyelinating injury, Pdgfra^CreERT:Rpl22^HA mice exhibited HA labeling in OPCs, with a gradual increase in oligodendrocyte labeling during remyelination. In contrast, Plp^CreERT:Rpl22^HA exhibited oligodendrocyte labeling in lesions and throughout the CNS parenchyma, presenting a challenge in distinguishing newly generated oligodendrocytes during remyelination from pre-existing oligodendrocytes. Notably, HA expression was induced in oligodendrocytes, but not OPCs in demyelinated lesions of Plp^CreERT:Rpl22^HA mice even when the demyelinating injury was conducted several days after tamoxifen had cleared. This suggests a potential regulation of gene expression in OPCs in demyelinated lesions, in which Rpl22^HA translation may be prevented until oligodendrocyte differentiation occurs. Overall, the RiboTag reporter demonstrates high sensitivity and stability, and its potential application should be carefully considered in relation to the experimental model, timeline in which it will be used, and cell tracking conditions.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2513885"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Brain Endothelial Cell Caveolin-1/CXCL10 Axis Promotes T Cell Transcellular Migration Across the Blood-Brain Barrier.","authors":"Troy N Trevino, Ali A Almousawi, Remy Martins-Goncalves, Andrea Ochoa-Raya, KaReisha F Robinson, Genesis L Abad, Leon M Tai, Suellen D Oliveira, Richard D Minshall, Sarah E Lutz","doi":"10.1080/17590914.2025.2472070","DOIUrl":"10.1080/17590914.2025.2472070","url":null,"abstract":"<p><p>The mechanisms that govern whether T cells cross blood-brain barrier (BBB) endothelium by transcellular versus paracellular routes are unclear. Caveolin-1 is a membrane scaffolding and signaling protein associated with transcellular transmigration through the endothelial cytoplasm. Here, we report that the neuroinflammatory chemokine CXCL10 induced transcellular, caveolar transmigration of CXCR3+ CD4+ T cells. Specifically, data revealed that CXCL10-induced transcellular transmigration requires expression of Caveolin-1 and ICAM-1 in brain endothelial cells and of the CXCL10 receptor, CXCR3, and LFA-1 in T cells. Moreover, Caveolin-1 promoted CXCL10 aggregation into brain endothelial cytoplasmic stores, providing a mechanism for activation and recruitment of CXCR3+ T cells to migrate at cytoplasmic locations, distal to cell-cell junctions. Consistent with our <i>in vitro</i> data, genetic ablation of Caveolin-1 reduces infiltration of CXCR3+ CD4+ T cells into the CNS in experimental autoimmune encephalomyelitis. Our findings establish a novel mechanism by which brain endothelial cells utilize Caveolin-1 dependent CXCL10 intracellular stores to license T cells for transcellular migration across the blood-brain barrier.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2472070"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12047051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596193","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":"Sex Affects Cognitive Outcomes in HIV-1 Tat Transgenic Mice: Role of CCR5.","authors":"Chloe A Simons, Sarah Kim, Yun K Hahn, Ama Boake-Agyei, Sara R Nass, Phu Vo, Kurt F Hauser, Pamela E Knapp","doi":"10.1080/17590914.2024.2447338","DOIUrl":"10.1080/17590914.2024.2447338","url":null,"abstract":"<p><p>People living with HIV (PLWH) experience HIV-associated neurocognitive disorders (HAND), even though combination antiretroviral therapy (cART) suppresses HIV replication. HIV-1 transactivator of transcription (HIV-1 Tat) contributes to the development of HAND through neuroinflammatory and neurotoxic mechanisms. C-C chemokine 5 receptor (CCR5) is important in immune cell targeting and is a co-receptor for HIV viral entry into CD4+ cells. Notably, CCR5 has been implicated in cognition unrelated to HIV infection. Inhibition of CCR5 has been shown to improve learning and memory. To test whether CCR5 is involved in cognitive changes in HAND, we used a non-infectious, transgenic model in which HIV-1 Tat is inducibly expressed. Well-powered cohorts of male and female mice were placed on a diet containing doxycycline to induce Tat expression for 8-wks. Males showed Tat-mediated deficits in the Barnes maze test of spatial learning and memory; females showed no impairments. Deficits in the males were fully reversed by the CCR5 antagonist, maraviroc (MVC). Tat-mediated deficits were not found in novel object recognition or contextual fear conditioning in either sex. Based on earlier work, we hypothesized that MVC might increase brain-derived neurotrophic factor (BDNF), which is essential in maintaining synaptodendritic function. MVC did increase the mBDNF to proBDNF ratio in males, perhaps contributing to improved cognition.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2447338"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977399","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":"P-glycoprotein and Alzheimer's Disease: Threats and Opportunities.","authors":"Joseph Jr Asante, Steven W Barger","doi":"10.1080/17590914.2025.2495632","DOIUrl":"10.1080/17590914.2025.2495632","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects more than 50 million people worldwide. One of the hallmark features of AD is the accumulation of amyloid β-peptide (Aβ) protein in the brain. P-glycoprotein (P-gp) is a membrane-bound protein expressed in various tissues, including the cerebrovascular endothelium. It plays a crucial role in the efflux of toxic substances, including Aβ, from the brain. Aberrations in P-gp levels or activity have been implicated in the pathogenesis of AD by promoting the accumulation of Aβ in the brain. Therefore, modulating the P-gp function represents a promising therapeutic strategy for treating AD. P-gp has multiple substrate binding sites, creating the potential for substrates to fall into complementation groups based on these sites; two substrates in the same complementation group may compete with one other, but two substrates in different groups may exhibit cooperativity. Thus, a given P-gp substrate may interfere with Aβ efflux whereas another may promote clearance. These threats and opportunities, as well as other aspects of P-gp relevance to AD, are discussed here.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2495632"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12140463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959945","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":"Proliferating Microglia Exhibit Unique Transcriptional and Functional Alterations in Alzheimer's Disease.","authors":"Nàdia Villacampa, Heela Sarlus, Paula Martorell, Khushbu Bhalla, Sergio Castro-Gomez, Ana Vieira-Saecker, Ilya Slutzkin, Kristian Händler, Carmen Venegas, Róisín McManus, Thomas Ulas, Marc Beyer, Eran Segal, Michael T Heneka","doi":"10.1080/17590914.2025.2506406","DOIUrl":"10.1080/17590914.2025.2506406","url":null,"abstract":"<p><p>Proliferation of microglia represents a physiological process, which is accelerated in several neurodegenerative disorders including Alzheimer disease (AD). The effect of such neurodegeneration-associated microglial proliferation on function and disease progression remains unclear. Here, we show that proliferation results in profound alterations of cellular function by providing evidence that newly proliferated microglia show impaired beta-amyloid clearance in vivo. Through sorting of proliferating microglia of APP/PS1 mice and subsequent transcriptome analysis, we define unique proliferation-associated transcriptomic signatures that change with age and beta-amyloid accumulation and are characterized by enrichment of immune system-related pathways. Of note, we identify the DEAD-Box Helicase 3 X-Linked (DDX3X) as a key molecule to modulate microglia activation and cytokine secretion and it is expressed in the AD brain. Together, these results argue for a novel concept by which phenotypic and functional microglial changes occur longitudinally as a response to accelerated proliferation in a neurodegenerative environment.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2506406"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12140498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092761","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":"Assessment of Phase-Dependent Alterations in Cortical Glycolytic and Mitochondrial Metabolism Following Ischemic Stroke.","authors":"Shokofeh Rahimpour, Ethan Meadows, John M Hollander, Kate Karelina, Candice M Brown","doi":"10.1080/17590914.2025.2488935","DOIUrl":"10.1080/17590914.2025.2488935","url":null,"abstract":"<p><p>Maintaining optimal brain metabolism supports neuronal function, synaptic communication, and cognitive processes. During ischemic stroke, brain metabolism and cellular bioenergetics within the neurovascular unit are disrupted, emphasizing the significance of understanding the physiology and pathology of the stroke brain. The objective of this study was to quantify and compare phase-dependent changes in glycolysis and oxidative phosphorylation following ischemic stroke by using the Seahorse XFe24 Analyzer. Since there are limited established methods to quantify glycolytic activity in brain tissue, we optimized the accuracy and reproducibility of extracellular acidification rate (ECAR) measurement by increasing the incubation time following exposure to each reagent. Following optimization, we quantified both ECAR and the oxygen consumption rate (OCR), a measure of oxidative phosphorylation, in cortical brain tissue punches corresponding to the penumbra from mice subjected to ischemic stroke. ECAR and OCR were quantified in tissue punches from the injured (ipsilateral) and the non-injured (contralateral) hemispheres at 48 hours, 7 days, and 14 days post-stroke. Normalized ECAR measurements showed elevated glycolytic activity in the ipsilateral and contralateral hemispheres at 7 days post-stroke compared to other time points. In contrast, normalized OCR measurements showed a modest increase in basal respiration within the ipsilateral hemispheres between 48 hours and 14 days post-stroke. In summary, the results demonstrate that ischemic stroke results in a distinct phase-dependent metabolic phenotype in both cortical hemispheres that persists up to 14 days after injury.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2488935"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12140487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975226","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":"Advances in Research on Exosomal miRNAs in Central Nervous System Diseases.","authors":"Guangli Feng, Xiaoqian Lan, Shiyi Qin, Yuting Shi, Qinxi Zhao, Qing Li, Lianmei Zhong","doi":"10.1080/17590914.2025.2465546","DOIUrl":"10.1080/17590914.2025.2465546","url":null,"abstract":"<p><p>Neurological diseases present a wide range of conditions, intricate diagnosis and treatment processes, and complex prognostic considerations. Therefore, research focusing on the diagnosis and treatment of these diseases is crucial. Exosomal miRNAs are small RNA molecules enclosed in membrane vesicles, released by cells and known to play roles in the development of various neurological disorders. They also serve as specific biomarkers for these conditions. Drawing on extensive research on exosomal miRNAs in diseases like stroke, Alzheimer's, epilepsy, Parkinson's, and neuroregeneration, this paper provides a comprehensive review of the relationship between exosomal miRNAs and neurological diseases. We strive to offer current and detailed theoretical understandings to help with the diagnosis and treatment of these disorders.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2465546"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12140465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750503","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":"Neurons Are Not All the Same: Diversity in Neuronal Populations and Their Intrinsic Responses to Spinal Cord Injury.","authors":"Justin R Siebert, Kiersten Kennedy, Donna J Osterhout","doi":"10.1080/17590914.2024.2440299","DOIUrl":"10.1080/17590914.2024.2440299","url":null,"abstract":"<p><p>Functional recovery following spinal cord injury will require the regeneration and repair of damaged neuronal pathways. It is well known that the tissue response to injury involves inflammation and the formation of a glial scar at the lesion site, which significantly impairs the capacity for neuronal regeneration and functional recovery. There are initial attempts by both supraspinal and intraspinal neurons to regenerate damaged axons, often influenced by the neighboring tissue pathology. Many experimental therapeutic strategies are targeted to further stimulate the initial axonal regrowth, with little consideration for the diversity of the affected neuronal populations. Notably, recent studies reveal that the neuronal response to injury is variable, based on multiple factors, including the location of the injury with respect to the neuronal cell bodies and the affected neuronal populations. New insights into regenerative mechanisms have shown that neurons are not homogenous but instead exhibit a wide array of diversity in their gene expression, physiology, and intrinsic responses to injury. Understanding this diverse intrinsic response is crucial, as complete functional recovery requires the successful coordinated regeneration and reorganization of various neuron pathways.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2440299"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998934","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}