ASN Neuro[JOURNAL]
Sun
200 papers
The CEMIP Hyaluronidase is Elevated in Oligodendrocyte Progenitor Cells and Inhibits Oligodendrocyte Maturation.
Peters A, Yasuhara K, Su W … +6 more , Matsumoto S, Pham P, Banine F, Harris E, Back SA, Sherman LS
ASN Neuro · 2025 · PMID 41361922 · Full text
Central nervous system (CNS) demyelination occurs in numerous conditions including multiple sclerosis (MS). CNS remyelination involves recruitment and maturation of oligodendrocyte progenitor cells (OPCs). Remyelination...
Central nervous system (CNS) demyelination occurs in numerous conditions including multiple sclerosis (MS). CNS remyelination involves recruitment and maturation of oligodendrocyte progenitor cells (OPCs). Remyelination often fails in part due to the inhibition of OPC maturation into myelinating oligodendrocytes (OLs). Digestion products of the glycosaminoglycan hyaluronan (HA), generated by hyaluronidase activity, block OPC maturation and remyelination. Here, we aimed to identify which hyaluronidases are elevated in demyelinating lesions and to test if they influence OPC maturation and remyelination. We find that the Cell Migration Inducing and hyaluronan binding Protein (CEMIP) is elevated in demyelinating lesions in mice with experimental autoimmune encephalomyelitis during peak disease when neuroinflammatory mediators, including tumor necrosis factor-α (TNFα), are at high levels. CEMIP expression is also elevated in demyelinated MS patient lesions. CEMIP is expressed by OPCs, and TNFα induces increased CEMIP expression by OPCs. Both increased CEMIP expression and HA fragments generated by CEMIP block OPC maturation into OLs. CEMIP-derived HA fragments also prevent remyelination . These data indicate that CEMIP blocks remyelination by generating bioactive HA fragments that inhibit OPC maturation. CEMIP is therefore a potential target for therapies aimed at promoting remyelination.
Global Deficiency of Alzheimer's Disease Risk Gene Reduces Pathological Tau in a Mouse Model of Systemic Inflammation.
Dadras S, Bhaskar K
ASN Neuro · 2025 · PMID 41353558 · Full text
Brain inflammation is strongly associated with neurodegeneration in Alzheimer's disease (AD) and related tauopathies. We have previously demonstrated that microglia-derived interleukin-1β (IL-1β) induces tau hyperphospho...
Brain inflammation is strongly associated with neurodegeneration in Alzheimer's disease (AD) and related tauopathies. We have previously demonstrated that microglia-derived interleukin-1β (IL-1β) induces tau hyperphosphorylation in a cell-autonomous manner and depends on activating the IL-1 receptor (IL-1R1) signaling pathway. IL-1 receptor accessory protein (IL-1RAcP) is a co-receptor for IL-1R1 and is essential for the IL-1R1 receptor function and downstream signaling. Genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) in the gene that have been shown to increase AD risk. Here, we demonstrate that global and neuron-specific isoform deficiency of IL-1RAcP regulates hyperphosphorylated tau levels in a lipopolysaccharide (LPS)-induced mouse model of systemic inflammation. Notably, while global reduced pS202(AT8) and pT231 (AT180) tau levels, neuron-specific IL-1RAcP (IL-1RAcPb) deficiency specifically increased total tau levels. Together, these results suggest that IL-1RAcP is an important regulator of tau hyperphosphorylation relevant to AD and related tauopathies.
Dual Stages of Alcohol-Related Cerebral White Matter Degeneration Reviewed: Early-Stage Stress/Neuroinflammation Versus Late-Stage Impaired Insulin/IGF Signaling Through Akt-mTOR-Review.
de la Monte SM, Sutherland G
ASN Neuro · 2025 · PMID 41108371 · Full text
Long-term effects of alcohol-related brain damage (ARBD) include neurocognitive and neurobehavioral dysfunctions with neurodegeneration. White matter (WM) is notably targeted across the lifespan yet relatively little is...
Long-term effects of alcohol-related brain damage (ARBD) include neurocognitive and neurobehavioral dysfunctions with neurodegeneration. White matter (WM) is notably targeted across the lifespan yet relatively little is known about the stages, mechanisms, and consequences of myelin and axonal loss. In alcohol-related liver disease, early pathology is reversible, but with chronic heavy alcohol exposures, disease progresses with degeneration, and ultimately organ failure. Similarly, WM ARBD also develops in two broad stages. The early stages of WM ARBD are likely mediated by vascular dysfunction with tissue swelling, oligodendrocyte dysfunction, myelin loss, neuroinflammation, and oxidative stress. The chronic progressive stage is linked to metabolic dysfunction related to impairments in insulin and insulin-like growth factor signaling through Akt-mechanistic target of rapamycin (mTOR) pathways that mediate oligodendrocyte survival and function, myelin homeostasis, and blood-brain-barrier (BBB) integrity. We hypothesize that early-stage WM ARBD may be largely reversible by abstinence and anti-oxidant/anti-inflammatory measures, whereas late-stage ARBD requires strategies to restore WM/oligodendrocyte metabolic function via insulin sensitizer, antioxidant, anti-inflammatory, and myelin homeostasis/normalization support. Multi-pronged, overlapping but distinct therapeutic strategies are needed to reduce the impact and long-term health consequences of chronic progressive WM ARBD.
Combined Treatment with Minocycline and an mGluR5 Antagonist Alters Resting EEG Spectral Power, but Not Sound-Evoked Responses, in a Mouse Model of Fragile X Syndrome.
Kassir MH, Lovelace JW, Binder DK … +2 more , Ethell IE, Razak KA
ASN Neuro · 2025 · PMID 41097999 · Full text
Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism-like behaviors. Glutamatergic mGluR5 receptors and matrix metalloproteinase-9 (MMP-9) are therapeutic targets to treat FXS, but cl...
Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism-like behaviors. Glutamatergic mGluR5 receptors and matrix metalloproteinase-9 (MMP-9) are therapeutic targets to treat FXS, but clinical trials targeting each of these pathways have not been successful. Here, we tested if the electroencephalography (EEG) phenotypes associated with FXS are reversed with a novel combination of treatments affecting the two pathways. knockout (KO) mice were given 10 days of CTEP (mGluR5 antagonist) alone or in combination with minocycline (MMP-9 inhibitor). EEG was recorded during resting (no acoustic stimulation) and during sound presentations (to produce sound-evoked EEG) at 1 day and 10 days after the beginning of treatment administration to test acute effects and potential tachyphylaxis. In pre-treatment WT and KO mice comparisons, we replicated previously published KO mouse EEG phenotypes including elevated power in the resting gamma band, elevated single trial power, and reduced phase-locking to spectrotemporally dynamic auditory stimuli. We found that CTEP treatment alone did not show any benefit compared to vehicle in KO mice after either 1 or 10 days of treatment. CTEP + minocycline reduced resting gamma band power in the KO mice to a greater extent than vehicle at both treatment time points. There were no effects on sound-evoked responses. These data suggest that combined CTEP and minocycline treatment alters resting EEG measures while each treatment administered separately does not yield similar changes. High power in broadband gamma frequency correlates with irritability, stereotyped behaviors, and hyperactivity in FXS patients, suggesting a combination of drugs that reduce mGluR5 and MMP-9 activity may be beneficial in FXS.
Demystifying The Myelin Ratio: Its Origin, Derivation and Interpretation.
Gow A
ASN Neuro · 2025 Jul · PMID 40819219 · Full text
Most studies involving myelin ratios over the past 120 years assume this metric enumerates differences in myelin thickness (larger ratio = thinner myelin) with axon or fiber diameter. And, moreover, such changes are di...
Most studies involving myelin ratios over the past 120 years assume this metric enumerates differences in myelin thickness (larger ratio = thinner myelin) with axon or fiber diameter. And, moreover, such changes are directly correlated with internodal function (conduction velocity). However, such assumptions are warranted only in the absence of experimental errors and artifacts (i.e. under theoretical conditions). In reality, ratios can easily under- or overestimate the rate of change for this relation in excess of 10%, especially for small caliber fibers. Typical analyses of myelin internodes rely on an explicit mathematical model, where D is axon diameter and D is fiber diameter (myelin plus axon). Shown recently and herein, this model approximates normal physiological conditions only when the axon-fiber diameter relation is directly proportional, whence it is concordant with the axomyelin unit model. However, in transient or non-steady states (development/aging, disease or myelin plasticity) with linear but not directly proportional relations, ratios may not accurately describe myelin structure. Acceptance of this counterintuitive assertion is predicated on a detailed understanding of the ratio - its origins, properties and the biology represented - which has been heretofore unexplored. In light of such ratio limitations, and toward consistency with experimental data, two more reliable metrics are proposed, the myelin ratio and the cline. But irrespective which of metric is preferred , the analysis herein shows that the axon-to-fiber diameter ratio under normal physiological conditions is a constant for all fiber diameters.
Dysregulated Expression of Inflammasome and Extracellular Matrix Genes in -ALS/FTD Microglia.
Thiry L, Pulimood NS, Tang YM … +1 more , Stifani S
ASN Neuro · 2025 · PMID 40776416 · Full text
Hexanucleotide repeat expansion (HRE) in the non-coding region of the gene is the most prevalent mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The HRE contributes to neuron degenera...
Hexanucleotide repeat expansion (HRE) in the non-coding region of the gene is the most prevalent mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The HRE contributes to neuron degeneration in ALS/FTD through both cell-autonomous mechanisms and non-cell autonomous disease processes involving glial cells such as microglia. The molecular mechanisms underlying the contribution of -HRE microglia to neuron death in ALS/FTD remain to be fully elucidated. In this study, we generated microglia from human -HRE and isogenic iPSCs using three different microglia derivation methods. RNA sequencing analysis reveals a cell-autonomous dysregulation of extracellular matrix (ECM) genes and genes involved in pathways underlying inflammasome activation in -HRE microglia. In agreement with elevated expression of inflammasome components, conditioned media from -HRE microglia enhance the death of -HRE motor neurons implicating microglia-secreted molecules in non-cell autonomous mechanisms of HRE pathology. These findings suggest that aberrant activation of inflammasome-mediated mechanisms in -HRE microglia results in a pro-inflammatory phenotype that contributes to non-cell autonomous mechanisms of motor neuron degeneration in ALS/FTD.
Identifying Lanthionine Ketimine Derivatives for Maturation and Proliferative Effects in Oligodendrocyte Progenitor Cells.
McDonald Z, Tandon A, Denton TT … +7 more , Taneja M, Rocha J, Dupree JL, Paez PM, Cheli VT, Tumuluri SG, Feinstein DL
ASN Neuro · 2025 · PMID 40692140 · Full text
Previous studies have shown that lanthionine ketimine ethyl ester (LKE) reduces clinical scores in the experimental autoimmune encephalomyelitis (EAE) mouse model of Multiple Sclerosis, induces differentiation of oligode...
Previous studies have shown that lanthionine ketimine ethyl ester (LKE) reduces clinical scores in the experimental autoimmune encephalomyelitis (EAE) mouse model of Multiple Sclerosis, induces differentiation of oligodendrocyte progenitor cells (OPCs) in vitro, and accelerates remyelination following cuprizone induced demyelination. In a search for derivatives with greater efficacy to induce OPC maturation or proliferation, we screened a panel of 2-alkyl and 3-phosphonate substituted LK derivatives. Incubation of Oli-neu oligodendrocyte cells with 2--butyl- or 2--hexyl-LKE-phosphonate reduced spontaneous cell death, increased proliferation, and increased maturation. These were associated with changes in corresponding mRNA levels of Olig2, PLP, and O4. These derivatives also reduced cell death and increased proliferation and maturation in primary mouse OPCs. The increased hydrophobicity of these derivatives suggests these will be better candidates for testing effects in animal models of Multiple Sclerosis and other demyelinating diseases.
Cortical Stimulation-Based Transcriptome Shifts on Parkinson's Disease Animal Model.
Nam J, Shin H, You C … +4 more , Baeg E, Kim JG, Yang S, Han MR
ASN Neuro · 2025 · PMID 40522886 · Full text
Parkinson's disease is the second most prevalent neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons. Significant improvements in gait balance, particularly in step length and velo...
Parkinson's disease is the second most prevalent neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons. Significant improvements in gait balance, particularly in step length and velocity, were observed with less invasive wireless cortical stimulation. Transcriptome sequencing was performed to demonstrate the cellular mechanism, specifically targeting the primary motor cortex, where stimulation was applied. Our findings indicated that 38 differentially expressed genes (DEGs), initially downregulated following Parkinson's disease induction, were subsequently restored to normal levels after cortical stimulation. These 38 DEGs are potential targets for the treatment of motor disorders in Parkinson's disease. These genes are implicated in crucial processes, such as astrocyte-mediated blood vessel development and microglia-mediated phagocytosis of damaged motor neurons, suggesting their significant roles in improving behavioral disorders. Moreover, these biomarkers not only facilitate the rapid and accurate diagnosis of Parkinson's disease but also assist in precision medicine approaches.
Analysis of Oligodendrocyte Lineage Cell Progression with Cre-Mediated RiboTag Reporter Lines.
Melchor GS, Shah MS, Manavi Z … +5 more , Rosko LM, Hu J, Wang H, Baydyuk M, Huang JK
ASN Neuro · 2025 · PMID 40515465 · Full text
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...
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:Rpl22, Pdgfra:Rpl22, and Plp:Rpl22 mice. We found that NG2:Rpl22 displayed strong HA reporter expression in OLCs and neuronal subpopulations in the postnatal CNS. Tamoxifen administration into Pdgfra:Rpl22 and Plp:Rpl22 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:Rpl22 mice exhibited HA labeling in OPCs, with a gradual increase in oligodendrocyte labeling during remyelination. In contrast, Plp:Rpl22 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:Rpl22 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 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.
Proliferating Microglia Exhibit Unique Transcriptional and Functional Alterations in Alzheimer's Disease.
Villacampa N, Sarlus H, Martorell P … +11 more , Bhalla K, Castro-Gomez S, Vieira-Saecker A, Slutzkin I, Händler K, Venegas C, McManus R, Ulas T, Beyer M, Segal E, Heneka MT
ASN Neuro · 2025 · PMID 40387894 · Full text
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 prol...
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-glycoprotein and Alzheimer's Disease: Threats and Opportunities.
Asante JJ, Barger SW
ASN Neuro · 2025 · PMID 40264334 · Full text
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 bra...
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.
Assessment of Phase-Dependent Alterations in Cortical Glycolytic and Mitochondrial Metabolism Following Ischemic Stroke.
Rahimpour S, Meadows E, Hollander JM … +2 more , Karelina K, Brown CM
ASN Neuro · 2025 · PMID 40205986 · Full text
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 disr...
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.
G-Ratio Commentary-Why You've Been Doing It Wrong.
Fields RD, Dutta DJ
ASN Neuro · 2025 · PMID 40193278 · Full text
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Advances in Research on Exosomal miRNAs in Central Nervous System Diseases.
Feng G, Lan X, Qin S … +4 more , Shi Y, Zhao Q, Li Q, Zhong L
ASN Neuro · 2025 · PMID 40165664 · Full text
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...
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.
A Brain Endothelial Cell Caveolin-1/CXCL10 Axis Promotes T Cell Transcellular Migration Across the Blood-Brain Barrier.
Trevino TN, Almousawi AA, Martins-Goncalves R … +7 more , Ochoa-Raya A, Robinson KF, Abad GL, Tai LM, Oliveira SD, Minshall RD, Lutz SE
ASN Neuro · 2025 · PMID 40063988 · Full text
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 t...
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 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.
A Statistically-Robust Model of the Axomyelin Unit under Normal Physiologic Conditions with Application to Disease States.
Gow A, Dupree JL, Feinstein DL … +1 more , Boullerne A
ASN Neuro · 2025 · PMID 39883092 · Full text
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. Ind...
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 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 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 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.
Understanding the Myelin Ratio from First Principles, Its Derivation, Uses and Artifacts.
Gow A
ASN Neuro · 2025 · PMID 39854637 · Full text
In light of the increasing importance for measuring myelin ratios - the ratio of axon-to-fiber (axon + myelin) diameters in myelin internodes - to understand normal physiology, disease states, repair mechanisms and myel...
In light of the increasing importance for measuring myelin 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 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 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 ratio plots has zero slope, and it identifies the underlying causes of several data processing artifacts that can be mitigated by plotting 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.
Neurons Are Not All the Same: Diversity in Neuronal Populations and Their Intrinsic Responses to Spinal Cord Injury.
Siebert JR, Kennedy K, Osterhout DJ
ASN Neuro · 2025 · PMID 39819292 · Full text
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 gli...
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.
New Atg9 Phosphorylation Sites Regulate Autophagic Trafficking in Glia.
Wang L, Yi S, Zhang S … +7 more , Tsai YT, Cheng YH, Lin YT, Lin CC, Lee YH, Wang H, Ho MS
ASN Neuro · 2025 · PMID 39807990 · Full text
We previously identified a role for dAuxilin (dAux), the fly homolog of Cyclin G-associated kinase, in glial autophagy contributing to Parkinson's disease (PD). To further dissect the mechanism, we present evidence here...
We previously identified a role for dAuxilin (dAux), the fly homolog of Cyclin G-associated kinase, in glial autophagy contributing to Parkinson's disease (PD). To further dissect the mechanism, we present evidence here that lack of glial dAux enhanced the phosphorylation of the autophagy-related protein Atg9 at two newly identified threonine residues, T62 and T69. The enhanced Atg9 phosphorylation in the absence of dAux promotes autophagosome formation and Atg9 trafficking to the autophagosomes in glia. Whereas the expression of the non-phosphorylatable Atg9 variants suppresses the lack of dAux-induced increase in both autophagosome formation and Atg9 trafficking to autophagosome, the expression of the phosphomimetic Atg9 variants restores the lack of Atg1-induced decrease in both events. In relation to pathophysiology, Atg9 phosphorylation at T62 and T69 contributes to dopaminergic neurodegeneration and locomotor dysfunction in a PD model. Notably, increased expression of the master autophagy regulator Atg1 promotes dAux-Atg9 interaction. Thus, we have identified a dAux-Atg1-Atg9 axis relaying signals through the Atg9 phosphorylation at T62 and T69; these findings further elaborate the mechanism of dAux regulating glial autophagy and highlight the significance of protein degradation pathway in glia contributing to PD.
Sex Affects Cognitive Outcomes in HIV-1 Tat Transgenic Mice: Role of CCR5.
Simons CA, Kim S, Hahn YK … +5 more , Boake-Agyei A, Nass SR, Vo P, Hauser KF, Knapp PE
ASN Neuro · 2025 · PMID 39805095 · Full text
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)...
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.
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